GEOVAX, INC. — Department of Health and Human Services SBIR Phase I: NIAID

Description

DESCRIPTION provided by applicant The proposed project Directed Lineage Immunizations for Eliciting Broadly Neutralizing Antibody tests the directed lineage D L approach to HIV vaccination using clade C immunogens With a D L vaccine a series of progressively evolved Env immunogens are used to drive development of a broadly neutralizing antibody bnAb response which is important because of its ability to prevent the establishment of latent reservoirs and viral persistence No vaccine has yet achieved such a response but studies of naturally infected humans have shown that in patients in whom a transmitted founder T F Env has stimulated an unmutated common ancestor UCA for bnAb the co evolution of virus and B cells can lead to somatic mutations that generate bnAb The GeoVax directed lineage vaccine is designed to reproduce the series of mutations in Env that led to development of bnAb to the CD binding site CD bs in one well studied clade C infected patient Duke CHAVI patient The vaccines to be tested include four recombinant Modified Vaccinia Ankara rMVA viral vaccines each expressing non infectious Virus Like Particles VLP and two recombinant gp protein vaccines The MVA expressed VLPs display Env in a native conformation while the gp s are potent at boosting MVA elicited Ab responses The vaccines will be produced and then tested in rhesus macaques use of the rhesus model is essential because the rhesus germline sequence for the UCA for bnAb to the CD bs is orthologous to the human UCA Two different regimens will be tested In the D L regimen animals will be immunized with four different rMVA vaccines expressing Env proteins from sequential nodes for the elicitation of bnAb to the CD bs in patient the rMVA immunizations will be followed by two immunizations with gp vaccine corresponding to the most evolved Env In the T F regimen animals will be immunized with rMVAs and gp s containing only the T F sequence Serum samples will be taken from the animals throughout the study at time points designed to capture peak and contracted responses The sera will be tested for magnitude specificity and breadth of elicited binding antibody bAb and neutralizing antibody nAb ELISAs will be performed with gp and gp antigens to demonstrate the overall magnitude and subunit specificity of the immune response and also with antigens specifically designed to quantify immune responses to the CD binding site CD bs Testing for nAb will be performed by our collaborator Dr David Montefiori The nAb testing will determine the magnitude and breadth of the nAb response and will determine the CD bs specificity of elicited nAb GeoVax will also test elicited Ab for avidity a potential correlate of protection Analysis of the data will allow GeoVa to characterize the immune responses and to determine whether the new vaccine design successfully elicited a bnAb response whether the protein boost increased bnAb titer and whether the D L approach improved responses relative to the T F immunizations If the D L is successful at broadening the neutralizing Ab response it will be advance in clinical testing If te D L approach does not broaden the nAb response the simpler T F vaccine will be advanced into the clinic PUBLIC HEALTH RELEVANCE This project addresses the unmet need for an HIV vaccine capable of raising a broadly neutralizing antibody response which is important to prevent HIV from infecting a personandapos s cells and entering a latent state in which it is invisible to the immune system Included in the project are the production and animal testing of six vaccine products four recombinant viral vaccines and two recombinant protein vaccines designed to be used in sequence to drive the development of broadly neutralizing antibodies This project is an important test of a new and innovative approach to HIV prevention and will advance novel vaccines towards the clinic