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Principal Investigator: George N. Pavlakis
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2020
Award: $1,511,661
Funding agency: National Cancer Institute
An important goal of this project continues to be the generation and testing of maximally efficient expression vectors for specific antigens. Our hypothesis is that the DNA vaccine dose is suboptimal for many human applications; therefore, increased efficiency is necessary for practical human DNA vaccines. We have generated a set of optimized expression vectors for HIV and SIV. HIV vectors are developed for eventual human clinical trials. These vectors are studied in macaques for immunogenicity and ability to protect against challenge with Simian/Human Immunodeficiency Virus hybrid viruses (SHIV). Several of our vectors have been used in clinical trials sponsored by our previous CRADA collaborator (Wyeth) and more recently by us through the support of NIAID. In parallel, SIV expression vectors are developed and studied in the most faithful model system for human AIDS, i.e., challenge of Rhesus macaques by SIV, a virus closely related to HIV, which causes very similar pathology to human AIDS. Our results have shown that optimized DNA expression vectors in the absence of any other form of vaccine boosting are able to protect rhesus macaques from high viremia after challenge with a highly pathogenic SIVmac251 challenge. In addition, we have developed powerful new DNA and protein co-immunization protocols that increase the magnitude, rapidity and longevity of immune responses. These vaccines were shown to protect macaques from infection in several studies. In this reporting period, we have shown 67% per challenge protection of macaques from SHIV pathogenic challenge using an optimized DNA and protein vaccination. These results suggest novel avenues for clinical development, especially to advance the concept of co-immunization with DNA and protein at the same site and time. To further improve vaccine efficiency we study the intrinsic properties of the different candidate antigens. We take advantage of the ability to manipulate the form of expressed antigen by recombinant DNA technology. We have shown that modulating the form, stability and cellular fate of the DNA-produced antigens has profound effects on their immunogenicity and the type of response generated. We perform comparative studies to develop optimal forms of several antigens. Results in rhesus macaques verified that the form of expressed antigen affects the type and magnitude of immune response. We study several different antigen forms to achieve optimal immune response and to address the variability of HIV strains circulating worldwide. We compare the immune response generated by either mixes of native antigens, mosaics, centralized and consensus candidates, and also antigens containing only conserved elements of HIV proteins. Such comparisons may lead to further optimization of a protective immune response. We have recently shown, in collaboration with the Human Retrovirus Pathogenesis Section (Dr. Felber), that vaccination with conserved elements vaccine constructs has the ability to alter the hierarchy of immune response and to direct it towards conserved elements, which are found in all HIV clades. On the basis of these data, we have completed a clinical trial (HVTN 119) to test the ability of Conserved Element vectors to provide broader immune response in humans. The methodology and vectors used for DNA vaccination of macaques have shown that we produce a strong, broad and long-lasting immunity, which is able to contain virus replication and prevent disease development. We also showed that DNA in combination with an adjuvanted protein delays or prevents infection after repeated low dose virus challenge. This DNA and protein combination vaccine does not use live recombinant vectors (usually employed by other AIDS vaccine programs) and may provide practical advantages. DNA vaccination is emerging as a strong and most effective vaccination procedure for the development of cellular immunity in humans, based on clinical trials using the same methods and vectors we co-developed for macaques. These results strongly suggest that DNA vaccination will have many practical clinical applications. In addition to prophylactic vaccination against AIDS, the same methodologies were used in therapeutic vaccination protocols. A strong boost of cellular immune responses and subsequent control of viremia was observed in therapeutically immunized macaques, suggesting that therapeutic vaccination may contribute to long-term virus control. These results have also implications for the development of methods to apply DNA vaccine methodology to therapeutic cancer vaccines. We wish to combine therapeutic vaccination with additional methods to boost immune response and specific cell killing by cytotoxic cells. We therefore will use hetIL-15 to further boost cytotoxic cells responses based on our completion of studies demonstrating the safety of hetIL-15 in infected macaques. We have shown that inclusion of hetIL-15 in therapeutic vaccination results in high levels of cytotoxic cells. We also developed vaccine formulations that greatly enhance Antibody Dependent Cellular Cytotoxicity (ADCC) as an additional mechanism to eliminate virus-infected cells. We apply these new tools to identify optimal therapeutic protocols able to suppress or eliminate virus in infected subjects.
Terms: <AACTG><ACTG><AIDS><AIDS Vaccines><AIDS Virus><AIDS clinical trial group><AIDS vaccine><Ab-dependent cellular cytotoxicity><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><Address><Adjuvant><Affect><Animal Model><Animal Models and Related Studies><Antibody-Dependent Enhancement><Antigenic Determinants><Antigens><Antineoplastic Vaccine><Binding Determinants><Biologic Models><Biological Models><CRADA><Cancer Vaccines><Cancers><Cell Body><Cell Mediated Immunology><Cell-Mediated Immunity><Cells><Cellular Immunity><Clinical Trials><Codon><Codon Nucleotides><Collaborations><Combination Vaccines><Combined Vaccines><Communicable Diseases><Comparative Study><Consensus><Cooperative Research and Development Agreement><Cytotoxic cell><DNA><DNA Therapy><DNA Vaccines><DNA delivery><Data><Deoxyribonucleic Acid><Development><Disease><Disorder><Dose><Electroporation><Elements><Epitopes><Formulation><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transfer Clinical><Generations><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic Intervention><Goals><HIV><HIV Vaccine Trials Network><HVTN><Human><Human Immunodeficiency Viruses><Humoral Immunities><Hybrids><IMiD><Immune mediated therapy><Immune modulatory therapeutic><Immune response><Immune system><Immunity><Immunization><Immunize><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically Directed Therapy><Immunomodulators><Immunostimulation><Immunotherapeutic agent><Immunotherapy><Infection><Infection prevention><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><K lymphocyte><LAV-HTLV-III><Lead><Legal patent><Length of Life><Liposomal><Liposomes><Longevity><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Malignant Neoplasms><Malignant Tumor><Methodology><Methods><Modality><Model System><Modern Man><Molecular><Mosaicism><NIAID><NK Cells><Naked DNA Vaccines><National Institute of Allergy and Infectious Disease><Natural Killer Cells><Neoplasm Vaccines><Non-Polyadenylated RNA><Patents><Pathogenesis><Pathogenicity><Pathology><Pathway interactions><Pb element><Plasmids><Prevent infection><Procedures><Property><Proteins><Protocol><Protocols documentation><RNA><RNA Gene Products><Recombinant DNA Technology><Recombinant DNA Vaccines><Recombinants><Reporting><Retroviral Antigen gag Protein><Retroviridae><Retroviruses><Rhesus Macaque><Rhesus Monkey><Ribonucleic Acid><SHIV><SIV><Safety><Simian Immunodeficiency Viruses><Site><Technology><Testing><Therapeutic><Time><Tumor Vaccines><VAC-TX><Vaccination><Vaccine Therapy><Vaccines><Viral><Viral Vaccines><Viral gag Proteins><Viremia><Virus><Virus Replication><Virus-HIV><Virus-Retrovirus><Work><acquired immunodeficiency syndrome clinical trial group><allergic/immunologic body system><allergic/immunologic organ system><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody-based immunity><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><base><cell killing><cellular development><clinical applicability><clinical application><clinical development><cytokine><deliver DNA><develop a vaccine><development of a vaccine><developmental><electroporative delivery><expression vector><gag Antigens><gag Gene Products><gag Polyproteins><gag Protein><gene electrotransfer><gene therapy><gene-based therapy><genetic therapy><genetically engineered><genomic therapy><group specific antigen><heavy metal Pb><heavy metal lead><host response><human DNA><immune drugs><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulators><immune modulatory agents><immune modulatory drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenicity><immunologic preparation><immunologic therapeutics><immunomodulating agents><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><improved><in vivo><life span><lifespan><mRNA Stability><malignancy><member><method development><model of animal><model organism><mosaic disorders><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><new technology><novel><novel technologies><pathogen><pathway><plasmid vaccine><prevent><preventing><programs><prophylactic><response><simian HIV><simian human immunodeficiency virus><therapeutic vaccination><tool><vaccine delivery><vaccine development><vaccine for cancer><vaccine formulation><vector><vector vaccine><viraemia><viral multiplication><viral replication><viral sepsis><virus multiplication><virusemia>