Optimization of a DNA Subunit Regimen for an HIV Vaccine

DESCRIPTION provided by applicant Our primary approach to develop an effective prophylactic vaccine against HIV utilizes a novel immunogen called the Full Length Single Chain FLSC that consists of gp derived from HIV BaL genetically linked via a amino acid linker to the D D domains of human CD Rhesus macaques were inoculated with rhFLSC a surrogate version of FLSC that contains CD derived from rhesus macaques The rhFLSC provided significant protection against rectal challenge with multiple low doses of R tropic and heterologous SHIV P These observations propelled FLSC into preclinical development and evaluation in a phase clinical trial supported by BMGF MHRP NIAID Consistent with the observations made in the RV clinical trial the protection we observed waned as the antibody titers dropped The presence of significant populations of single function T cells secreting IFN or IL also appeared to inversely correlate with the protection generated by rhFLSC subunit Our collaborators found that the simultaneous coadministration of pDNA and protein dramatically heightens the potency and extends the lifespan of the antibody response Vaccination with pDNA expressing antigen and IL administered by electroporation in macaques induces multifunctional T cells that are known to correlate with protection that could also improve the efficacy provided by FLSC subunit Our goal here is to build upon these observations and determine if a pDNA subunit combination vaccine can enhance the quality and durability of the immune response necessary to provide andgt efficacy after year post vaccination Our phase objective is to rank order FLSC DNA subunit immunization regimens based on the quality and durability of the immune response in mice Using the top regimens defined in Phase I we will determine if the selected vaccination regimen provides protection from SHIV challenge that is superior to that observed in RV and remains effective out to at least one year post vaccination through the following phase II specific aims Rank order FLSC DNA subunit immunization regimens based on the quality and durability of the immune response in macaques Rank order FLSC DNA subunit immunization regimens based on their efficacy against SHIV P challenge By the end of this project we should identify a regimen that extends the longevity of humoral and cellular responses to provide andgt efficacy upon heterologous SHIV P challenge after year Should this optimized delivery regimen fulfill the phase II goals it will be fast tracked into human clinical trials The objective of this project is to identify optimal an optimal delivery regimen for an HIV DNA vaccine Such an optimized delivery regimen is needed for DNA vaccines to combat the HIV epidemic