PfCSP- VLPs
Project Name: PfCSP-VLPs
Candidate Malaria Vaccine : PfCSP-VLPs formulated with or without adjuvant
Indication: Vaccine candidate for Plasmodium falciparum malaria
Route of administration: Intra muscular
Development Phase: Early development of vaccine candidate and testing in small animals for immunogenicity
Objective: The objective of project is to develop a recombinant PfCSP-VLP as vaccine candidate using CPLB-Novavax propriety platform. This candidate after lab scale production will be tested for immunogenicity in small animals with various human compatible adjuvants. Immune sera raised will be tested for various in-vitro and in-vivo functional assays in various academic laboratories. Most potent combination of PfCSP VLP and adjuvant will be taken forward for process and clinical development.
Current Status: PfCSP–VLPs has been produced and small animals have been immunized with various human compatible adjuvants. Immune sera raised are now being tested in various in-vitro and in-vivo functional assays to check the efficacy of vaccine candidate in animal models.
Biological Rationale: PfCSP based malaria vaccinesPfCSP has been a leading target for development of pre-erythrocytic stage malaria vaccines. It’s a 44 kDa protein that is abundantly expressed on the surface of P.falciparum sporozoites. The central region of PfCSP contains NANP and NVDP repeat tetra-peptides that serve as crucial immuno-dominant B-cell epitopes. While vaccine development efforts using recombinant proteins, synthetic peptides and viral vectors to deliver PfCSP were not successful, fusion of hepatitis B surface antigen (HBsAg) with PfCSP to produce virus-like-particles (VLPs) referred to as RTS,S has yielded encouraging results. Protection was, however, only achieved when RTS,S was formulated with potent adjuvants such as AS02A and AS01B. In phase III field trials, approximately 30%–50% of children and infants immunized with RTS,S are protected from clinical malaria. These studies have validated PfCSP as a vaccine candidate. However, given that RTS,S provides only 30-50% protection against P. falciparum malaria, there is plenty of room for improvement.
Virus Like particles (VLPs)
VLP-based vaccines represent a new class of recombinant vaccines that mimic the virus structure but lack internal genetic material rendering them non-infectious but highly immunogenic. They present to the immune system an array of pathogen-associated molecular patterns (PAMPs) and initiate innate immune responses through pattern recognition receptors on host immune cells that recognize PAMPs leading to robust adaptive and inflammatory responses to control infection. Pattern recognition receptors, such as Toll-like receptors on the cell surface, recognize PAMPs from viral proteins and nucleic acids. Bridging of the innate and adaptive immune responses is mediated by activation of antigen-presenting cells, namely the dendritic cells stimulating T- and B-cell immunity. VLPs, when taken up by human dendritic cells, activate these cells, which leads to strong cytotoxic lymphocyte responses by cross-presentation via MHC class I molecules as well as robust antibodyresponses.
The influenza VLP platform developed by CPLB-Novavax is being used to develop vaccines for seasonal flu, pandemic flu and RSV. VLP has been well tolerated and has been shown to be immunogenic in five Phase I/II trials. This also includes the swine A/H1N1 2009 pandemic flu VLP vaccine tested in a Phase II clinical trial in about 3500 subjects in Mexico during the 2009 – 2010 pandemic (Novavax;manuscript submitted). The influenza VLP platform has also been used to produce chimeric.VLPs to develop a vaccine for RSV. The RSV VLP vaccine is presently being tested in Phase I Clinical trial under a US FDA IND. In this project attempt has been made to develop a more effective PfCSP based pre-erythrocytic malaria vaccine by improving on the CSP construct used in RTS,S and by using an alternate VLP platforms.
Key Organizations
| Organization | Role |
| DBT, Government of India | Funded the project |
| International Centre for Genetic Engineering and Biotechnology, New-Delhi, India | Design the candidate vaccine and conducting animal immunogenicity studies |
| Cadila Pharmaceutical Limited, Biologics (CPLB) Ahmedabad India and its partner Novavax INC USA | Development of Lab Scale VLP |
| Infectious Disease research Institute (IDRI), Washington, USA | Manufacturer of adjuvant GLA SE |
| Malaria Vaccine Development Program, New Delhi, India | Coordination and management of the project |
| PATH MVI | Providing reagents and access to reference laboratory like Johns Hopkins University Laboratory |