P.falciparum, PfCSP-VLP
Project Name: PfCSP-VLPs
Candidate Malaria Vaccine: PfCSP-VLPs formulated with or without adjuvant
Route of administration: Intramuscular
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 has been tested for immunogenicity in small animals with various human compatible adjuvants. Immune sera raised has been tested for 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 havebeen produced in baculovirus expression system and immunogenicity of PfCSP-VLPs with human compatible adjuvants or without an adjuvant have been tested in small animals.Immune sera raised were tested in various in-vitro and in-vivo functional assays to check the efficacy of vaccine candidate in animal models. Three PfCSP-VLP constructs (here the partial CSP construct with 14 NANP repeats), namely, M1-PfCSP Short, VP6-PfCSP Short and VP6-PfCSP Long were successfully produced and expressed as VLPs by Novavax, USA. These VLP constructs were then formulated with two potent adjuvants, Alhydrogel and GLA-SE and tested in pre-clinical immunogenicity studies in small animals. Results show that the VLPs, especially VP6-PfCSP Long,are robust in inducing high antibody responses against CSP antigen that were functionally active and successful in reducing the parasite load in the liver stages as shown by in vivo studies in mice..The study demonstrated that while PfCSP-VLPs are highly immunogenic, it may be possible to improve the immunogenicity further by including all 37 NANP repeats in the VLP construct.These studies provide the basis for taking the VLPs forward into clinical development and produce VLP based nanoparticles that would express full length PfCSP and induce potent neutralizing antibodies.
Biological Rationale:
PfCSP based malaria vaccines
PfCSP has been a leading target for development of pre-erythrocytic stage malaria vaccines. It is 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 (M1 protein) VLP and rota virus (VP6 protein) VLP platforms developed by CPLB-Novavaxhavebeen used to develop alternate strategy to express PfCSP that can be advantageous over the current HBsAg platform used in RTS,S.
VLP project received funding from the Department of Biotechnology (DBT), Government of India.
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 at the Johns Hopkins University |