Engineering the Immune Response of a Self-replicating and Adjuvanting RNA HIV-1Vaccine

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Principal Investigator: Amit Praful Khandhar
Organization: HDT BIO CORPORATION
Fiscal Year: 2023
Award: $940,253
Funding agency: National Institute of Allergy and Infectious Diseases

Project Summary/Abstract
A key requirement for HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bNAbs)
targeting the HIV-1 envelope (Env) spike. The BG505 SOSIP.664 gp140 soluble timer is engineered to display
conformational epitopes recognized by several bNAbs but not non-neutralizing antibodies. The prototype SOSIP
vaccine is currently being evaluated in two clinical trials. An effective messenger RNA (mRNA) vaccine
expressing BG505 SOSIP.664 will complement the clinical vaccine and open a path to heterologous
immunization strategies to elicit immune responses defined by increased breadth and magnitude. Recent
achievements in mRNA vaccines is a result of advancements in nanoparticle delivery technologies. We recently
reported immunogenicity of a replicating RNA (repRNA) vaccine encoding the spike (S) protein of SARS-CoV-
2; this vaccine, delivered with a novel Lipid Inorganic Nanoparticle (LION) carrier, induced potent binding and
neutralizing antibodies in both mice and non-human primates. In the proposed R61/R33 application, we will
investigate and optimize attributes of the LION formulation to engineer the immunity of a BG505 SOSIP.664
expressing repRNA vaccine (repRNA-SOSIP.664). The goal is to identify a lead vaccine and administration route
that promotes B cell differentiation and maturation needed for induction of high affinity Env antibodies that confer
protection in a macaque SHIV challenge model. The proposed work will be performed with a three-way
collaboration between Dr. Amit Khandhar at HDT Bio, Dr. Noah Sather at Seattle Children’s Research Institute
(SCRI) and Prof. Deborah Fuller at the University of Washington (UW). Proposed activities in the R61 phase will
include (specific aim 1) optimizing the repRNA/LION platform for intramuscular (IM), intradermal (ID) and
intranasal (IN) delivery and (specific aim 2) screening immunogenicity of vaccine candidates in mouse and
rabbit models. In the R33 phase, we will advance (specific aim 3) one or more lead vaccine candidates to
evaluate protective efficacy in a macaque SHIV challenge model. Milestones in the R61 phase are (milestone
1) identification of formulations that target lymph nodes or remain at injection site, (milestone 2) develop an
optimized LION formulation for intranasal delivery of repRNA, (milestone 3) one or more repRNA/LION
immunization regimens that induce neutralizing antibodies greater than or equal to the BG505 SOSIP.664
protein/adjuvant vaccine. Using clearly defined go/no-go metrics for each milestone we will determine transition
to the R33 phase of the project. Milestones in the R33 phase are (milestone 1) one or more vaccine regiment
affords statistically significant protection compared to controls in a macaque SHIV challenge model as measured
by one or more protection measures and (milestone 2) one or more immune responses in vaccinated animals
correlate with one or more protection measure.

Terms: <0-11 years old><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><AIDS Virus><Achievement><Achievement Attainment><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adjuvant><Affinity><Animals><Antibodies><Antibody Response><Antibody titer measurement><Antigen Presentation><Antigenic Determinants><Antigens><B blood cells><B cell><B cell differentiation><B cells><B lymphocyte differentiation><B-Cells><B-Lymphocytes><B-cell><Benchmarking><Best Practice Analysis><Binding><Binding Determinants><Biodistribution><Blood Serum><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><Cell Maturation><Child><Child Youth><Children (0-21)><Clinical><Clinical Trials><Collaborations><Complement><Complement Proteins><Complex><Domestic Rabbit><Drops><Early-Stage Clinical Trials><Engineering><Epitopes><Formulation><Future><Goals><HIV><HIV-1><HIV-1 vaccine><HIV-I><HIV1><HIV1 vaccine><Histology><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immune><Immune response><Immunes><Immunity><Immunization><Immunize><Immunological response><Injections><Intramuscular><LAV-HTLV-III><Lead><Lipids><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic nodes><Macaca><Macaque><Measures><Messenger RNA><Mice><Mice Mammals><Modeling><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Non-Polyadenylated RNA><Normal Tissue><Normal tissue morphology><Nucleic Acid Vaccines><Oryctolagus cuniculus><Pathway interactions><Pb element><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Proteins><RNA><RNA Gene Products><RNA replication><RNA vaccine><RNA-based vaccine><Rabbits><Rabbits Mammals><Regimen><Reporting><Research Institute><Ribonucleic Acid><Route><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SHIV><Serum><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Site><Squalene><Technology><Testing><Universities><Vaccinated><Vaccination><Vaccines><Viral><Viral Burden><Viral Load><Viral Load result><Virus><Virus-HIV><Washington><Work><antibody titering><benchmark><compare to control><comparison control><conformation><conformational><conformational state><conformationally><conformations><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><deliver vaccines><design><designing><determine efficacy><develop a vaccine><develop vaccines><development of a vaccine><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><engineered immune system><evaluate efficacy><examine efficacy><heavy metal Pb><heavy metal lead><host response><immune engineering><immune system response><immunization strategy><immunoengineering><immunogen><immunogenicity><immunoresponse><kids><lymph gland><lymph nodes><lymphnodes><mRNA><mRNA vaccine><mRNA-based vaccine><manufacture><manufacturing capabilities><manufacturing capacity><nano emulsion><nano particle><nano particle delivery><nano-sized particle><nanoemulsion><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><neutralizing antibody><non-human primate><nonhuman primate><novel><nucleic acid-based vaccine><pathway><phase I protocol><pre-clinical development><preclinical development><protective efficacy><protein expression><prototype><response><screening><screenings><simian HIV><simian human immunodeficiency virus><timeline><trafficking><vaccination strategy><vaccine candidate><vaccine delivery><vaccine development><vaccine formulation><vaccine immune response><vaccine immunogenicity><youngster>