Prevention of AIDS

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Our recognition of the fundamental mechanisms of mRNA expression, exemplified by the regulated expression of HIV, provided the basics for our interest in developing preventive HIV DNA based vaccine strategies. Attractive features of the DNA platform lie in its simplicity, versatility, stability, with repeated administration without vector immunity, being a non-replicating vaccine and not association with adverse effects. Several DNA vaccines are currently in clinical trials against HIV and cancer, and there is a licensed DNA vaccine against dog melanoma. We are testing immunogenicity of SIV and HIV DNA vaccines in mice and selected DNA candidates advance to the macaque model. Some of our successful candidates have been moved to clinical trials. Because intramuscular injection of DNA induces relatively low immune responses in macaques and humans, we are testing additional delivery methods, including in vivo electroporation and liposomes. We reported that electroporation dramatically increased the efficiency of DNA delivery in naive macaques, leading to greatly augmented antigen expression and resulting in the induction of highest levels of T cell responses. Our DNA vaccine includes the cytokine IL-12 DNA (expressed from an optimized. plasmid DNA) as adjuvant and we reported increased magnitude and quality of the responses. Importantly, we reported the dissemination of the DNA vaccine induced T cell responses to mucosal sites including rectal and vaginal mucosa, the portal of entry of HIV. We also found that DNA induced immune responses show extraordinary longevity in vaccinated macaques detectable for several years after the last vaccination. DNA vaccination elicits moderate humoral immune responses in macaques. Using DNA-only vaccination, we found that our optimized DNA vaccine vectors are able to induce potent immune responses able to protect from high viremia. We showed that a protein boost can induce higher levels of Ab. We reported that co-delivery of DNA+protein, using either unadjuvanted or adjuvanted protein, in the same muscle at the same time increased antibody production and mucosal dissemination. DNA+Protein co-immunization is superior to vaccination with either of the two individual components in eliciting humoral immune responses. We have previously shown that combination of that simultaneous vaccination DNA+Protein vaccination induces potent humoral responses able to significantly delay or prevent virus acquisition and improve virological control of the highly pathogenic SIV challenge. We now report a comparison of immunogenicity and protective efficacy of an HIV vaccine comprised of env and gag DNA and Env proteins by co-administration of the vaccine components in the same muscles or by separate administration of the DNA and Protein components in contralateral sites with 20 female rhesus macaques in each group. The 6-valent vaccine included DNA plasmids expressing membrane-anchored gp145 Env, representing six sequentially isolated Env sequences from an HIV infected individual (CH505), and matching GLA-SE-adjuvanted gp120 Env proteins. Interestingly, only macaques in the co-administration vaccine group were protected against SHIV CH505 acquisition after repeated low dose intravaginal challenge and showed 67% risk reduction per exposure. Macaques in the co-administration group developed higher Env-specific humoral and cellular immune responses. Non-neutralizing Env antibodies, antibodies mediating cellular cytotoxicity (ADCC) and antibodies with high binding to FcgammaRIIIa were associated with decreased transmission risk. These data suggest that simultaneous recognition, processing and presentation of DNA + Env protein in the same draining lymph nodes play a critical role in the development of protective immunity. We hypothesize that optimization of immunogens to better target the rare B cell precursor, combined with the Co-administration of vaccine vector and protein in same draining lymph nodes could provide an immunological advantage over current protocols, resulting in significantly improved protection and we are in the process of further exploring this. Our aim has been to design and test a vaccine regimen focusing the immune response to targets associated with infection prevention. The RV144 vaccine trial revealed a correlation between reduced risk of HIV infection and the level of non-neutralizing antibody (Ab) responses targeting specific epitopes in the second variable domain (V2) of the HIV gp120 envelope (Env) protein, suggesting this region as a target for vaccine development. To favor induction of V2-specific Abs, we developed a vaccine regimen that included priming with DNA expressing an HIV V1V2 trimeric scaffold immunogen followed by booster immunizations with a combination of DNA and protein in rhesus macaques. Priming vaccination with DNA expressing the HIV recombinant subtype CRF01_AE V1V2 scaffold induced higher and broader V2-specific Ab responses than vaccination with DNA expressing CRF01_AE gp145 Env. Abs recognizing the V2 peptide that was reported as a critical target in RV144 developed only after the priming immunization with V1V2 DNA. The V2-specific Abs showed several non-neutralizing Fc-mediated functions, including antibody-dependent phagocytosis (ADCP) and C1q binding. Importantly, robust V2-specific Abs were maintained upon boosting with gp145 DNA and gp120 protein co-immunization. We reported that priming with DNA expressing the trimeric V1V2 scaffold alters the hierarchy of humoral immune responses to V2 region epitopes, providing a method for more efficient induction and maintenance of V2-specific Env Abs associated with reduced risk of HIV infection. We showed that V1V2 scaffold DNA priming immunization provides a method to focus immune responses to the desired target region, in the absence of immune interference by other epitopes. This induced immune responses with improved recognition of epitopes important for protective immunity, namely, V2-specific humoral immune responses inversely correlating with HIV risk of infection in the RV144 trial.