Lymphatic filariasis due to Brugia malayi and Wucheraria bancrofti is a debilitating disease that affects more than 200 million people worldwide. Mass chemotherapy is effective in reducing infection intensity in some endemic areas, suggesting that control against this infection is feasible. In endemic areas a group of individuals broadly defined as endemic normal (EN), remain refractive to infection despite frequent exposure to the infection. These individuals carry circulating protective antibodies that could kill infective larvae (L3) of B. malayi and W. bancrofti in vitro. Mechanism of this immune killing is not known. Nevertheless, these findings show that active immunization against lymphatic filariasis is possible, provided the antigens that generated the protective immune responses could be identified. Using an interative screening of a phage display expression library of B. malayi L3 with EN sera, we identified three antigens (BmALT-2, BmVAH and BmCol-4) that are specifically responsible for generating the protective immune responses. Homologues of all three antigens were subsequently cloned from W. bancrofti and show significant cross-reactivity. Preliminary immunization studies showed that significant protection (40-72%) could be achieved in mice and jird models following a prime (DNA) boost (recombinant protein) approach using all three antigens. Experiences from vaccine development against malaria suggest that a multivalent vaccine confer significantly higher protection than a single antigen alone. Therefore, in this application we are proposing to develop a multivalent vaccine comprising the three protective antigens (ALT-2, VAH and BmCol-4). There are four specific aims to this proposal. Since antigenic poly morphism has been reported in filariasis, Aim 1 will first determine whether there is any antigenic polymorphism in the three candidate vaccine antigens isolated from wild collected parasites. Preliminary studies show that both cells and antibodies are important in the protective responses in EN individuals. Therefore, Aim 2 will identify the characteristics of the protective immune responses to the vaccine constructs in human. Based on the information gathered from aims 1 and 2, Aim 3 will construct a multivalent vaccine consisting of hybrid gene of the three candid antigens in pVAX vector and fusion protein for boosting.
Aim 4 will then evaluate and optimize the multivalent vaccine in animal models and determine the optimum protocol for human vaccination. The proposed studies are based on solid preliminary data and are hypotheses driven. Results from these studies, we believe will advance our knowledge towards developing a defined vaccine against lymphatic filariasis in the human.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064745-04
Application #
7926939
Study Section
Special Emphasis Panel (ZRG1-IMM-K (12))
Program Officer
MO, Annie X Y
Project Start
2007-08-01
Project End
2013-07-31
Budget Start
2010-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$376,337
Indirect Cost
Name
University of Illinois at Chicago
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Khatri, Vishal; Chauhan, Nikhil; Vishnoi, Kanchan et al. (2018) Corrigendum to ""Prospects of developing a prophylactic vaccine against human lymphatic filariasis - evaluation of protection in non-human primates"" [Int. J. Parasitol. 48 (2018) 773-783]. Int J Parasitol 48:1071
Khatri, Vishal; Chauhan, Nikhil; Vishnoi, Kanchan et al. (2018) Prospects of developing a prophylactic vaccine against human lymphatic filariasis - evaluation of protection in non-human primates. Int J Parasitol 48:773-783
Chauhan, Nikhil; Banerjee, Priyankana; Khatri, Vishal K et al. (2017) Improving the efficacy of a prophylactic vaccine formulation against lymphatic filariasis. Parasitol Res 116:2821-2830
Dakshinamoorthy, Gajalakshmi; von Gegerfelt, Agneta; Andersen, Hanne et al. (2014) Evaluation of a multivalent vaccine against lymphatic filariasis in rhesus macaque model. PLoS One 9:e112982
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Dakshinamoorthy, Gajalakshmi; Samykutty, Abhilash Kumble; Munirathinam, Gnanasekar et al. (2013) Multivalent fusion protein vaccine for lymphatic filariasis. Vaccine 31:1616-22
Dakshinamoorthy, Gajalakshmi; Kalyanasundaram, Ramaswamy (2013) Evaluating the efficacy of rBmHAT?c as a multivalent vaccine against lymphatic filariasis in experimental animals and optimizing the adjuvant formulation. Vaccine 32:19-25
Dakshinamoorthy, Gajalakshmi; Munirathinam, Gnanasekar; Stoicescu, Kristen et al. (2013) Large extracellular loop of tetraspanin as a potential vaccine candidate for filariasis. PLoS One 8:e77394
Thirugnanam, Sivasakthivel; Munirathinam, Gnanasekar; Veerapathran, Anandharaman et al. (2012) Cloning and characterization of high mobility group box protein 1 (HMGB1) of Wuchereria bancrofti and Brugia malayi. Parasitol Res 111:619-27
Dakshinamoorthy, Gajalakshmi; Samykutty, Abhilash Kumble; Munirathinam, Gnanasekar et al. (2012) Biochemical characterization and evaluation of a Brugia malayi small heat shock protein as a vaccine against lymphatic filariasis. PLoS One 7:e34077

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