MEDICAL BIOTECHNOLOGY / Recombinant Diagnostics and Vaccines
Recombinant Virus-like-particles as Dengue vaccine candidate, Anti-dengue botanical drug development and Point-of-care multiplexed diagnostics
Description of Research
Recombinant dengue vaccine development-Dengue is a neglected mosquito-borne viral disease that is rapidly spreading globally. Dengue is prevalent in more than 100 countries in the world and is estimated to cause 390 million dengue infections per year with India alone contributing 34% of these infections. Dengue is caused by four serotypes of Dengue viruses (DENV-1, -2, -3 and -4) and all four DENV serotypes are now endemic in India. Dengue infections result in massive economic losses, strained health services, morbidity & mortality, especially among children. The development of a vaccine against dengue poses several challenges because immune response to the four DENV serotypes cross react and instead of cross-protection, enhance the disease. Although a limited use of live attenuated virus-based dengue vaccine has become available, it has several concerns. The WHO strongly recommends the development of next-generation dengue vaccines.
We have developed virus-like-particle (VLP) based Pichia pastoris expressed sub-unit vaccine candidate against dengue. This vaccine candidate is a tailored recombinant VLP based tetravalent vaccine candidate displaying host cell receptor binding domain, envelope domain III (EDIII), of all four serotypes on the VLPs. It has been found to elicit DENV neutralizing antibodies in mice and macaques. This vaccine candidate is expected to provide a competitive edge over others in all three critical parameters of safety, efficacy & affordability that define an ideal dengue vaccine. This project is being supported by Sun Pharma (Industrial Partner) and National Biopharma Mission, Government of India.
Anti-dengue Novel botanical drug development-Currently, there are no available antivirals, which presents a public health challenge in India and other parts of the world, including developed nations. The dengue menace warrants an urgent need for an affordable and efficacious antiviral. We utilized Ayurveda and bioassay guided approach to screening anti-dengue potential of selected botanical extracts as a solution to this problem. We found Cissampelos pareira (CIPA) to be highly potent against all four DENV serotypes. In collaboration with Sun Pharma, pre-clinical evaluations are on-going to comply with regulatory standards of India and other regulatory agencies for its registration. This would be followed up with clinical trials.
Genetically engineered biomolecules and viral diagnostics-In collaboration with other academic and industrial collaborators from India and Finland (supported by Wellcome Trust), novel recombinant proteins are being explored for developing highly sensitive multiplexed point-of-care assay system for the detection of blood borne infections in medical emergency situations. This research collaboration aims to produce a new technology concept which upgrades the performance of the currently used rapid-testing methodology with lateral flow assay (LFA) test kits to near PCR sensitivity, but with ease of immune assays. With the new technology, infectious diseases can be tested in near-patient conditions with high accuracy and reliability without sacrificing the affordability of the testing.
The Dengue vaccine technology developed by our team was licensed to Sun Pharma in 2016. Process scale-up was conducted in the Sun Pharma-affiliated Biotech company in Germany in 2019, and has been brought back to India for in-house development under the National Biopharma Mission, Gov. of India. A Sun Pharma GMP facility is being established in Bangalore and efforts are being made to reach Phase 1 efficacy trials. Preclinical tox-studies have been completed for the Dengue vaccine candidate, and the data is being analysed for moving forward to the next stage of trials. The co-development of the world’s first Botanical drug with Sun Pharma for the treatment of Dengue infection has successfully completed Phase 1 clinical trials. Phase 2 trials of this drug are ongoing at 16 trial sites in India, with a sample size of 676.
Rajpoot, R.K., Shukla, R., S., Arora, U., Swaminathan, Khanna, N. 2018. Dengue envelope-based ‘four-in-one’ virus-like particles produced using Pichia pastoris induce enhancement-lacking, domain III-directed tetravalent neutralising antibodies in mice. Scientific Reports volume 8, Article number: 8643 (2018) PubMed link
Shukla, R., Rajpoot, R.K., S., Arora, U., Poddar, A., Swaminathan, Khanna, N. 2018. Pichia pastoris-Expressed Bivalent Virus-Like Particulate Vaccine Induces Domain III-Focused Bivalent Neutralizing Antibodies without Antibody-Dependent Enhancement in Vivo. January 2018 | Volume 8 | Article 2644 PubMed lin
Ramasamy V., Arora U., Shukla R., Poddar A., Shanmugam R.K., White L.J., Mattocks M. M., Raut R., Perween A., Tyagi P., Silva A.D., Bhaumik S.K., Kaja M.K, Villinger F., Ahmed R., Johnston R., Swaminathan, Khanna, N. 2018. A tetravalent virus-like particle vaccine designed to display domain III of dengue envelope proteins induces multi-serotype neutralizing antibodies in mice and macaques which confer protection against antibody dependent enhancement in AG129 mice. PLoS Negl Trop Dis 12(1): e0006191 PubMed link
Khetarpal, N., Shukla, R., Rajpoot, R.K., Poddar, A., Pal, M., Swaminathan, S., Arora, U., Khanna, N. 2017. Recombinant Dengue Virus 4 Envelope Glycoprotein Virus-Like Particles Derived from Pichia pastoris are Capable of Eliciting Homotypic Domain III-Directed Neutralizing Antibodies. Am J Trop Med Hyg 96,126-134 PubMed link
Poddar, A., Ramasamy, V., Shukla, R., Rajpoot, R.K., Arora, U., Jain, S.K., Swaminathan, S., Khanna, N. 2016. Virus-like particles derived from Pichia pastoris-expressed dengue virus type 1 glycoprotein elicit homotypic virus-neutralizing envelope domain III-directed antibodies. BMC Biotechnol 16, 50 PubMed link
Talha, S.M., Salminen, T., Juntunen, E., Spangar, A., Gurramkonda, C., Vuorinen, T., Khanna, N., Pettersson, K. 2016. Europium nanoparticle-based simple to perform dry-reagent immunoassay for the detection of hepatitis B surface antigen. J Virol Methods 229, 66-69 PubMed link
R.K. Rajpoot, R. Shukla, U. Arora, N. Khanna. Tetravalent Dengue Vaccine And Processes Thereof. PCT/IN/2018/050352
R.K. Rajpoot, R. Shukla, U. Arora, N. Khanna. Tetravalent Dengue Vaccine And Processes Thereof. 201711034626
N. Khanna and V. Ramasamy. Vaccine. WO 2016/034974 A1
P.K. Bhatnagar, C. K. Katiyar, N. Khanna, D. J. Upadhyay, S. Swaminathan, K. Srinivas, N. Sharma, A. Kanaujia, R. Sood, S. Singhal, G. Shukla, R. Duggar, P. K. Pareek, Y. Singh, S. Khan, and R. Raut. Use of Cissampelos pariera extracts for treating dengue. US 20160243182 A1
[…] “Humanitas Research Hospital” discussing Immune responses and vaccination prospects with Navin Khanna, Translational Health, ICGEB New Delhi. Alessandro Marcello, Molecular Virology, ICGEB Trieste will pair with Milan Surjit, Translational […]