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Principal Investigator: Richard Thomas Wyatt
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2024
Award: $976,445
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
A broadly effective HIV vaccine remains a high priority to reduce the spread of this highly pathogenic virus in the
human population. Neutralizing antibodies, broadly cross-neutralizing are highly likely needed to be generated
from evolving vaccine candidate immunogens, either protein-based or mRNA-based. Recently, we have elicited
cross-neutralizing serum and serum IgG responses in all macaques immunized with a series of 4 recombinant
highly stable and homogeneous NFL trimers arrayed at high density on fully synthetic trimer-liposomes. Besides
serum cross-neutralization we now have compelling EMPEM apex densities (Ozorowski/Ward – HIVRAD
Structural Core C) to heterologous near-native protein trimers derived from tier 2 viruses not in the immunogen
series. In addition, we know have isolated monoclonal antibodies that possess long and tip-charged HCDR3s
that compete with PGT145 and VRC26 for trimer-binding. These data indicate that these neutralizing antibodies
are likely apex-directed, cross-neutralizing antibodies – a very significant accomplishment for the field. To launch
this study, we initially tested a set of NFL trimers available from the Wyatt lab for recognition by the germline-
reverted NHP bNAb RHA1 from George Shaw (Roark et al, Science 2021). Remarkably, the Q23 NFL displayed
detectable binding that was enhanced by multi-valent array on covalent trimer-liposomes. Accordingly, we used
Q23 NFL trimers and Q23 trimer-liposome (high-valency array) in SMNP adjuvant (Darrell Irvine) to elicit
autologous neutralization. We followed the Q23 NFL prime with heterologous boosting of trimers that are the
most sensitive to apex-directed bNAbs (ie, ZM233, see below). Using this prime:boost strategy we elicited
neutralization of multiple clinical isolates, including the well-studied CH505 transmitter/founder virus. At this
juncture, our initial apex-targeting vaccine experiment in NHPs appears to be quite successful. We have elicited
both autologous Q23, ZM233 and 1428 neutralization, as well as cross-neutralization of tier 2 isolates not in
the vaccine regimen. Accordingly, here, we propose to perform heterologous protection studies of the NFL-
trimer vaccinated NHPs by repetitive low-dose mucosal challenge with the well-characterized, clinical isolate,
transmitter-founder-based CH505 SHIV.
Terms: <7S Gamma Globulin><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adjuvant><Animals><Antibodies><Antigens><Apical><Autologous><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Back><Binding><Blood Serum><Budgets><Charge><Clinical><Clinical Treatment Moab><Collaborations><Control Animal><Data><Dorsum><Dose><Funding><Germ Lines><Grouping><HIV><HIV vaccine><HIV-1 vaccine><HIV/AIDS Vaccines><HIV1 vaccine><Hand><Human><Human Immunodeficiency Viruses><IgG><Immunity><Immunize><Immunoglobulin G><Interpersonal Communication><LAV-HTLV-III><Liposomal><Liposomes><Lymphadenopathy-Associated Virus><Macaca><Macaque><Maps><Mediating><Messenger RNA><Modern Man><Molecular Interaction><Monoclonal Antibodies><Mucosa><Mucosal Tissue><Mucous Membrane><NIH><National Institutes of Health><Personal Communication><Population><Proteins><Public Health><Recombinants><Regimen><SHIV><Science><Series><Serum><Testing><United States National Institutes of Health><Vaccinated><Vaccines><Viral Diseases><Virus><Virus Diseases><Virus-HIV><density><experiment><experimental research><experimental study><experiments><groupings><hands><human immunodeficiency virus vaccine><immunogen><immunogenicity><improved><mAbs><mRNA><monoclonal Abs><neutralizing antibody><non-human primate><nonhuman primate><novel><pathogenic virus><response><simian HIV><simian human immunodeficiency virus><vaccine candidate><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease><ward>