Conserved Element DNA Vaccine

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

An ideal HIV vaccine should provide protection against all HIV-1 variants. Thus, an important aspect of HIV vaccine development is the selection of immunogens, which has to take into consideration the diversity of the different HIV clades and the identification of the critical epitopes able to induce relevant immune responses, avoiding potential immunodominant "decoy" epitopes. Considering the diversity of the different HIV clades, we are focusing on highly conserved regions of HIV to induce immune responses to nearly invariable proteome segments, essential for the function of the virus, while excluding responses to variable and potentially immunodominant "decoy" epitopes (Kulkarni, PLoS One 9: e86254, 2014; Kulkarni, PLoS One 9: e111085, 2014; Hu, Hum. Vaccin. Immunother. 14: 2163, 2018). In proof-of-concept studies in mice and macaques, we demonstrated that immunization with Gag CE DNA elicits robust cellular and humoral immune responses including robust cytotoxic T cell responses targeting subdominant epitopes against CE, which cannot be achieved by vaccination with the full-length p55gag DNA and induces Priming with CE DNA and boosting with CE+gag DNA maximizes both magnitude and breadth (Kulkarni, PLoS One 9: e86254. 2014; Kulkarni, PLoS One 9: e111085, 2014; Hu, J. Immunol. 197: 3999, 2016). This DNA vaccine regimen induces potent memory responses that can be rapidly recalled 2 years later by CE DNA booster vaccinations (Hu, Hum. Gene Ther. 29: 1029-1043, 2018. Thus, we identified a novel and effective strategy to maximize responses against Gag and provide a novel strategy to shift the immunodominance hierarchy and to induce robust immune responses to subdominant epitopes, effectively targeting the Achilles' heel of the virus. We are currently expanding this concept to SARS-Co-V2. We further developed an SIV homolog of the CE and demonstrated that priming with CE DNA followed by CE+gag DNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth (Hu, J. Immunol. 197: 3999, 2016). These data mirror our findings from the HIV p24CE vaccine and provide us with a tool to explore the functional applications of the Gag CE DNA vaccine in the macaque model. SIV Gag CE-specific T cells are able to reduce viral infection (Hu, Hum. Vaccin. Immunother. 14: 2163-2177, 2018) and application of this CE DNA vaccine is expanded to our on-going therapeutic vaccine trials in the macaque model. We have translated the HIV CE DNA vaccine concept to the clinic in the HIV Vaccine Trial Network (HVTN)/DAIDS/NIAID-supported clinical trial (HVTN 119; NCT03181789) with the aim to test whether our p24CE DNA vaccine concept elicits superior breath and magnitude of Gag responses compared to the optimized immunogen comprising the complete p55Gag protein. This vaccine includes Profectus' GENEVAX IL-12 DNA as molecular adjuvant and in vivo electroporation as DNA delivery method, two vaccine components our research had shown to be of importance to induce potent T cell responses in macaques. HVTN 119 combines several of milestones (DNA expression vectors, adjuvants, and delivery) we have achieved over many years in vaccine development. This trial is now closed, and we are finalizing data analysis. In another on-going study, we have translated the Gag CE DNA vaccine in a phase I/IIb trial (ACTG A5369; NCT03560258) supported by the AIDS Clinical Trial Group, to be tested in HIV-infected persons under HAART. This trial is now closed, and we are finalizing data analysis. Together, HVTN119 and A5369 will allow us to explore the translation of our data from mice and macaques to humans and initial data analysis supports our achievement of this goal. These two trials offer another unique opportunity to directly compare the same vaccines in two different cohorts, naive and HIV-infected on ART, using the same methodology, and will provide novel insight in the development in immune responses comparing the two cohorts. The CE DNA vaccine regimen is being tested in a third trial NCT04357821 supported by amfAR and UCSF as part of a combinatorial therapy to induce an HIV remission. Our goal is to develop and test immunotherapeutic methods that can lead to virus reservoir reduction or elimination. We have further expanded the CE vaccine regimen in collaboration with CureVac, Inc. as an mRNA/lipid nanoparticle (LNP) formulation in the macaque model (Valentin, Frontiers Immunol, 2022). The mRNA/LNP formulation induced robust, durable antibody responses but low adaptive T-cell responses, a feature also shared with the current COVID-19 mRNA vaccine. On the other hand, the mRNA/LNP vaccine was able to strongly boost pre-existing cellular response suggesting that it could be useful in heterologous prime/boost modality and in immune therapeutic interventions against HIV infection or other chronic human diseases. Our studies have provided useful information about different nucleic acid vaccine platforms and guide further clinical development.