Multi Vaccine Development Program. Not For Profit Research Society

P.falciparum, JAIVAC-2

Project Name: JAIVAC - 2

Candidate Malaria Vaccine: JAIVAC-2 Vaccine (PfMSP-Fu24+ PfF2) formulated with Alhydrogel.

Route of administration: Intramuscular

Development Phase: Toxicity studies Ongoing at JRF, VAPI

Objectives: The objective of the project is to develop a recombinant combination blood stage malaria vaccine candidate. The candidate is undergoing for toxicity studies. Subsequently, the safety and immunogenicity of JAIVAC-2 will be evaluated in healthy Indian adult subjects in a Phase I clinical trial.

Current Status: Technology to manufacture JAIVAC-2 under cGMP conditions for use in toxicity studies and Phase I Clinical Trial has been transferred to Vaccine Technology Centre, Zydus Cadila Ahmedabad. The two antigens (PfMSPFu24 and PfF2) have been manufactured under cGMP and formulated with adjuvant Alhydrogel.

Biological Rationale: The first blood stage vaccine candidate of ICGEB tested in the human clinical trials, JAIVAC-1, was composed of a physical mixture of two recombinant proteins, namely, PfMSP-119, the 19 kD conserved, C-terminal region of PfMSP-1, and PfF2, the conserved, Duffy-binding-like (DBL) receptor-binding domain of PfEBA-175. Both PfMSP-119 and PfF2 play important roles in red cell invasion. Hence, JAIVAC-1 was expected to elicit antibody responses that would target two critical parasite proteins involved in invasion and was predicted to be effective at inhibiting blood stage parasite multiplication. In the immunogenicity analysis of Phase I clinical trial serum samples of healthy adult male volunteers showed good antibody response to PfF2, as measured by Enzyme Linked Immunosorbent Assay (ELISA). However, majority of volunteers displayed very poor antibody response against PfMSP-119 (PLOS one 2015 ). Based on these observations, proceeding to the next stage of clinical development with JAIVAC-1 did not seem to be a viable option. But, considering the important role played by Merozoite Surface protein -1 during RBC invasion, it was necessary to improve the immunogenicity of PfMSP-119 through a novel approach. ICGEB, therefore prepared a fusion chimera (MSP-Fu24) consisting of PfMSP-119 and an 11kDa region of PfMSP-3 (PfMSP-311) that contains both a T-helper (Th) epitope as well as B epitopes that are the targets of Antibody Dependent Cellular Inhibition (ADCI). Method for producing recombinant MSP-Fu24 in Escherichia coli has been well optimised. Pre-clinical studies in small animals have demonstrated that this approach not only improves significantly the antibody responses against PfMSP-119 that inhibit erythrocyte invasion by P. falciparum but also elicits antibody responses against PfMSP-3 that participate in ADCI of parasite growth. Immunization with MSP-Fu24 (PfMSP-119-PfMSP311 fusion protein) thus elicits protective immune responses by two entirely different mechanisms: while the antibody response to the C-terminal fragments of PfMSP-1 inhibits erythrocyte invasion, antibodies against MSP-3 elicit ADCI in a monocyte-dependent manner to inhibit blood stage parasite growth. JAIVAC-2, will contain a physical mixture of PfF2 and MSP-Fu24 protein and is expected to take advantage of different kinds of immune responses that each of the individual antigens, PfMSP-119, PfMSP-311 and PfF2 will generate when administered together. Considering that the antibodies produced by each of these will prevent clinical infection and disease by diverse mechanisms, it is possible that this approach will provide a novel vaccine candidate with high efficacy.

JAIVAC-2 project received funding from the Department of Biotechnology (DBT), Government of India for Manufacturing and Toxicity studies. The Phase I trial finding is committed by BIRAC

Key Organizations

Organization Role
DBT, Government of India Funded the project
International Centre for Genetic Engineering and Biotechnology, New-Delhi, India Discovered the candidate vaccine
ZydusCadila, Vaccine Technology Centre, Ahmedabad India cGMP manufacture of JAIVAC-2
Brenntag Biosector A/S, Denmark Manufacture of adjuvant Alhydrogel
Malaria Vaccine Development Program, New Delhi, India Sponsor's representative for overall management of the Technology Transfer for cGMP Manufacturing of JAIVAC-2 and Phase I clinical trial