ARTIFICIAL CELL TECHNOLOGIES INC — Department of Health and Human Services SBIR Phase II: NIAID

Description

DESCRIPTION provided by applicant This Phase II project will develop a novel synthetic microparticle vaccine for malaria using the T BT epitopes of the circumsporozoite CS protein of Plasmodium falciparum the causative agent of human malaria There is no approved vaccine for malaria a disease that causes up to million new infections and million deaths each year in the developing world Preclinical and clinical research has demonstrated that epitopes of the CS protein of the parasite sporozoite stage can elicit protective immunity The protective immunity consists of parasite neutralizing antibodies that act at the site of infection and in the bloodstream and specific cellular mechanisms which prevent release of erythrocytic stage parasite from the host liver In the successful Phase I project we utilized layer by layer LbL fabrication to produce synthetic microparticles loaded with T BT a fusion peptide comprising the antibody epitope of the central repeat region B and two T cell epitopes the T epitope which overlaps B and is conserved in all strains of P falciparum and the T epitope which is located near the C terminus of CS and is a universal epitope recognized by multiple HLA haplotypes LbL particles are made with entirely synthetic raw materials no biological components and elicit potent adaptive immune responses with minimal inflammatory adverse events Our Phase I work showed that microparticles bearing T BT were potently immunogenic in mice eliciting parasite neutralizing antibodies and T cells including effector cytotoxic cells specific for the T cell epitopes Mice immunized with T BT microparticles were protected from Plasmodium challenge We also showed that a simple modification of the microparticles with an innate immune stimulator TLR ligand Pam Cys increased the potency and efficacy of the vaccine candidate without triggering overt inflammatory events In the current project we will select the final development candidate by examining immunogenicity and efficacy of microparticles loaded with T BT or Pam Cys T BT in both the mouse and rhesus macaque models Efficacy in the rhesus model will be tested by passively immunizing na ve mice with purified Ig from the monkeys and challenging the mice with Plasmodium We will select the candidate that elicits the highest parasite neutralizing antibody activity and IFN cellular responses since these two mechanisms appear to be responsible for protection against Plasmodium infection The selected candidate will be advanced to preclinical development which will include development of analytical release assays and a manufacturing process and assessment of safety and tolerability in a GLP compliant rabbit study The specific methods and strategies of the Phase II development efforts will be guided by discussions with the Food and Drug Administration FDA in preparation for GMP manufacturing and release of drug product and submission of an Investigational New Drug IND application in a subsequent Phase III project PUBLIC HEALTH RELEVANCE This project utilizes an innovative particle fabrication technology to produce synthetic vaccines that provide protection from malaria The Phase I project demonstrated the feasibility of this approach by showing that the synthetic particle vaccines elicited protective immune responses in mice The Phase II project will make minor modifications to improve the potency and efficacy of the vaccines and initiate preclinical development activities necessary to enable human clinical studies