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Principal Investigator: BARBARA K FELBER
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2019
Award: $2,251,746
Funding agency: National Cancer Institute
Our recognition of the fundamental mechanisms 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 optimized 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 found 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. Combination of DNA+Protein induces potent humoral responses able to significantly delay or prevent virus acquisition and improve virological control of the highly pathogenic SIV challenge. To optimize vaccine-induced immunity and efficacy of the DNA+protein co-immunization vaccine regimen, a SIVmac251 based vaccine was compared using two TLR-4-based liposomal formulations as adjuvants (TLR-4+TLR-7 or TLR-4+QS21) in macaques, which resulted in induction of robust humoral immune responses with qualitative differences. Vaccinees were preferentially infected by SIVsmE660 transmitted founder T/F virus carrying the neutralization resistant A/K mutation, demonstrating a strong vaccine-induced sieve effect. SIVsmE660-specific systemic neutralizing antibody and mucosal antibodies targeting V2 region of Env correlated with delay in acquisition of the neutralization-sensitive virus and. V2-specific antibodies and cellular SIV-specific T cell responses contributed to control of viremia. Although both DNA+protein vaccine groups show delay of virus acquisition, the TLR4+7 adjuvanted vaccine induced stronger protective responses resulting in lower peak and chronic viremia. We are further exploring approaches to improve immunogenicity targeting the V2 epitopes to induce more effective responses. We also compared immunogenicity and protective efficacy of a DNA+Protein vaccine delivered following two different strategies: co-administration in the same site or separate delivery of DNA and protein in opposite anatomical sites. We found that the co-immunization induces higher vaccine-induced Env Ab and T cell responses. Importantly, only the co-immunization group showed significant delay in SHIV acquisition with a 67% reduction in per exposure acquisition risk relative to the controls after 15 weekly intravaginal challenges. These data indicate that simultaneous recognition of the two vaccine components (DNA and protein) by the draining lymph node plays a critical role in the development of protective immunity. We are identifying correlates of protection from disease development, which will provide critical information to further improve our vaccine approaches. The advantage of co-immunization vaccine regimens targeting immunogens to the same draining lymph node could be applicable to other vaccine modalities and other pathogens.
Terms: <AIDS><AIDS Virus><AIDS prevention><ATGN><Ab response><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acquired Immunologic Deficiency Syndrome><Adjuvant><Adverse effects><Anatomic><Anatomic Sites><Anatomic Structure, System, or Substance><Anatomic Structures and Systems><Anatomic structures><Anatomical Sciences><Anatomy><Anatomy Qualifier><Antibodies><Antibody Formation><Antibody Production><Antigenic Determinants><Antigens><Binding Determinants><Biology><Cancers><Canine Species><Canis familiaris><Chronic><Clinical Trials><Codon><Codon Nucleotides><DNA><DNA Vaccines><DNA delivery><Data><Deoxyribonucleic Acid><Development><Disease><Disorder><Dogs><Dogs Mammals><Edodekin Alfa><Electroporation><Epitopes><Formulation><Gene Expression><General Viruses><Genetic Alteration><Genetic Change><Genetic defect><HIV><HIV Infections><HIV Prevention><HIV vaccine><HIV/AIDS Vaccines><HIV/AIDS prevention><HTLV-III Infections><HTLV-III-LAV Infections><Homolog of Drosophila TOLL><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><IL-12><IL12><Immune response><Immunity><Immunization><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunostimulation><Individual><Interleukin-12><Intramuscular><Intramuscular Injections><LAV-HTLV-III><Length of Life><Liposomal><Liposomes><Longevity><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Macaca><Macaque><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Methods><Mice><Mice Mammals><Modality><Modeling><Modern Man><Molecular><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Muscle><Muscle Tissue><Mutation><NKSF><Naked DNA Vaccines><Natural Killer Cell Stimulatory Factor><Non-Polyadenylated RNA><Pathogenicity><Play><Prevention><Preventive><Proteins><QS 21><QS-21 Adjuvant><QS21><RNA><RNA Gene Products><Recombinant DNA Vaccines><Regimen><Relative Risks><Reporting><Resistance><Ribonucleic Acid><Role><SHIV><SIV><Simian Immunodeficiency Viruses><Site><Stimulon QS-21 Adjuvant><T cell response><TLR4><TLR4 gene><Testing><Time><Toll Homologue><Vaccinated><Vaccination><Vaccines><Viremia><Virus><Virus-HIV><antibody biosynthesis><base><canine><cytokine><deliver DNA><developmental><domestic dog><efficacy testing><electroporative delivery><expression vector><gene electrotransfer><genome mutation><host response><human immunodeficiency virus vaccine><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><improved><in vivo><interest><intramuscular drug administration><life span><lifespan><lymph gland><lymph nodes><mRNA Expression><malignancy><melanoma><mucosal site><muscular><neoplasm/cancer><neutralizing antibody><novel><pathogen><plasmid vaccine><prevent><preventing><protective efficacy><rectal><resistant><response><simian HIV><simian human immunodeficiency virus><social role><toll-like receptor 4><vaccine delivery><vaccine efficacy><vaccine-induced immunity><vaccine-induced protection><vaginal mucosa><vector><vector vaccine><viraemia><viral sepsis><virology><virusemia>