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Principal Investigator: Leonidas Stamatatos
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $800,602
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT PROJECT ONE
We have reported on the design of a germline-targeting recombinant (rec) HIV-1 Env-derived immunogen,
426c.Mod.Core-C4b, that activates naïve B cells that express germline VRC01-class BCRs and on “booster”
rec protein immunogen, HxB2.WT.Core-C4b, that improves the maturation of the VRC01-class antibodies
elicited by 426c.Mod.Core-C4b. This maturation is, however, incomplete and additional immunizations with
heterologous Envs, yet to be identified, will be necessary to complete the maturation process that leads to the
production of broadly neutralizing VRC01-class antibodies. The identification of such Envs will require
extensive experimentation. To expedite this process, we are exploring alternative vaccination methodologies to
rec protein immunizations, such as self-amplifying RNA (saRNA) vaccine platforms. RNA vaccines offer
several advantages over rec protein immunogens as the RNA immunogen sequences can easily be modified,
they are more easily produced, and they do not require extensive purification steps. Also, they are less
expensive and faster to GMP-manufacture and they do not require adjuvants. So far however, not much is
known on how the quality of anti-Env B cell and antibody responses elicited by saRNA vaccines and by
adjuvanted rec Env protein immunogens compare. To address this point, in this Scientific Project One, we will
characterize the VRC01 B cell and antibody responses elicited by the 426c.Mod.Core-C4b germline-targeting
Env and the HxB2.WT.Core-C4b boost Env when delivered by saRNA vaccines. We will compare these
responses to those generated by the corresponding adjuvanted rec protein nanoparticles. We will also
examine whether the form of the immunogen expressed by the saRNA vaccines (either as secreted protein
nanoparticles or as membrane-anchored proteins) influences the quality of the VRC01 B cell and antibody
responses. In addition, the qualities of the VRC01 B cell and antibody responses will be evaluated in the
following three prime-boost modalities: (a) saRNA prime and saRNA boost; (b) saRNA prime and rec protein
boost; and (c) rec protein prime and saRNA boost. We propose an accelerated immunization schedule that
relies on our expertise on VRC01-class antibodies, Env-immunogen-design, BCR analysis and antibody
characterization, as well as our expertise with saRNA vaccine modalities. Our proposed studies are central to
the goals of this IPCAVD grant.
Terms: <Acceleration><Address><Adjuvant><Affinity><Antibodies><Antibody Response><Antigens><Autologous><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding><Bypass><C4 b><C4b><Clinical Evaluation><Clinical Testing><Clinical Treatment Moab><Clinical Trials><Complement 4b><Complement C4b><Envelope Protein><Germ Lines><Goals><Grant><HIV-1><HIV-1 vaccine><HIV-I><HIV1><HIV1 vaccine><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Immunization><Immunization Schedule><Light><Membrane><Methodology><Modality><Molecular Interaction><Monoclonal Antibodies><Mutate><Non-Polyadenylated RNA><Photoradiation><Predisposition><Process><Production><Protein Secretion><Proteins><RNA><RNA Gene Products><RNA amplification><RNA vaccine><RNA-based vaccine><Recombinant Proteins><Recombinants><Reporting><Ribonucleic Acid><Somatic Mutation><Specificity><Susceptibility><Vaccination><Virus><clinical test><deliver vaccines><design><designing><env Antigens><env Gene Products><env Polyproteins><env Protein><immunization strategy><immunogen><improved><mAbs><mRNA vaccine><mRNA-based vaccine><manufacture><membrane structure><monoclonal Abs><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><prevent><preventing><research clinical testing><response><self assembly><somatic variant><vaccination strategy><vaccine delivery><vaccine platform>