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Principal Investigator: Leonidas Stamatatos
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2023
Award: $2,099,783
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT OVERALL
The main goal of our IPCAVD Program grant is to evaluate in humans self-amplifying mRNA
(saRNA) vaccines that express two HIV-1 Env-derived protein immunogens that activate and
initiate the maturation of VRC01-class B cell receptors (BCRs). The first immunogen,
426c.Mod.Core, was specifically designed to bind with high affinity to the unmutated (germline,
gl) forms of those BCRs as they are expressed on the surface of naïve B cells. The second
immunogen, HxB2.WT.Core, although unable to bind germline VRC01-class BCRs, binds the
VRC01-class BCRs that became activated by 426c.Mod.Core and have accumulated some
somatic mutations. As a result, the boost immunization with HxB2.WT.Core furthers the
maturation of the VRC01-class antibodies elicited by the 426c.Mod.Core. These observations
were made with the adjuvanted recombinant (rec) forms of these two immunogens. As mRNA-
based vaccines are less costly and more easily GMP-manufactured that rec proteins, we
believe that they will accelerate the preclinical and clinical evaluation of HIV-1 Env-derived
immunogens. Here, we propose to first compare preclinically the VRC01 B cell and antibody
responses elicited by these two Env immunogens when delivered by saRNA vaccines to those
elicited by the corresponding adjuvanted rec proteins. And then, if the results are promising, the
saRNA vaccines expressing the two immunogens will be GMP-manufactured for clinical
evaluation. As the 426c.Mod.Core adjuvanted rec protein will be evaluated clinically (phase I) in
the spring of 2022 (HVTN301) and the HxB2.WT.Core rec protein is currently being GMP
manufactured for a follow-up phase I clinical evaluation in 2023, we will be in a unique position
to compare the VRC01 B cell and antibody responses elicited by humans immunized with these
two HIV-1 Env-derived immunogens when delivered as adjuvanted rec proteins and as
expressed by saRNA vaccines. To accomplish our goals in this IPCAVD grant we will take
advantage of our expertise in immunogen-design and testing, expertise in the analysis of B cell
and antibody responses elicited by vaccination and during infection, our ability to rapidly
sequence BCR genes using high through put technologies, the availability of appropriate animal
models, our expertise in saRNA vaccine technology, our unique expertise in conducting clinical
testing of HIV-1 vaccines, the existing collaboration among the participating groups and the
documented expertise of the participants to successfully manage complex Programs.
Terms: <AIDS test><AIDS/HIV test><Acceleration><Active Follow-up><Adjuvant><Affinity><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Response><Antigens><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cell Receptor Binding><B-Cells><B-Lymphocytes><B-cell><Binding><Clinical><Clinical Evaluation><Clinical Protocols><Clinical Testing><Collaborations><Complex><Cyclic GMP><Development><Early-Stage Clinical Trials><Envelope Protein><Fred Hutchinson Cancer Research Center><Goals><Grant><Guanosine Cyclic Monophosphate><HIV Vaccine Trials Network><HIV test><HIV-1><HIV-1 test><HIV-1 vaccine><HIV-2 test><HIV-I><HIV1><HIV1 vaccine><HVTN><Health><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Human immunodeficiency virus test><Immune response><Immunization><Immunize><Immunological response><Individual><Infection><Infectious Diseases / Laboratory><Infectious Diseases Research><Investigation><Lead><Length><Membrane><Messenger RNA><Modern Man><Molecular Interaction><Mutate><Outcome><Participant><Pb element><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Position><Positioning Attribute><Production><Property><Proteins><Qualifying><R-Series Research Projects><R01 Mechanism><R01 Program><RNA vaccine><RNA-based vaccine><Receptor Gene><Recombinant Proteins><Recombinants><Research Grants><Research Institute><Research Project Grants><Research Projects><Self evaluation><Self-Examination><Self-Surveillance><Self-reflection><Somatic Mutation><Surface><Technology><Testing><Vaccination><Vaccines><Virus><active followup><cGMP><clinical test><cost><design><designing><developmental><env Antigens><env Gene Products><env Polyproteins><env Protein><first in man><first-in-human><follow up><follow-up><followed up><followup><heavy metal Pb><heavy metal lead><host response><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><improved><mRNA><mRNA vaccine><mRNA-based vaccine><manufacture><membrane structure><model of animal><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><phase I protocol><pre-clinical><pre-clinical evaluation><preclinical><preclinical evaluation><programs><research clinical testing><response><safety testing>