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Principal Investigator: Beatrice H Hahn
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2020
Award: $860,928
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
A central goal in HIV/AIDS vaccine research is the elicitation of broadly neutralizing antibodies (bNAbs). Here,
we propose to leverage three recent discoveries from our groups to generate novel envelope (Env) immunogens
that target the V1V2 region of the trimer apex. By studying the evolution of the HIV-1 Env glycan shield, we
discovered that unshielded regions (“glycan holes”) in transmitted founder (TF) Envs are negatively associated
with bNAb development, suggesting that strain-specific glycan holes delay or subvert bNAb development (1).
Generating bNAb sensitivity signatures to design novel Signature-based Epitope Targeted (SET) vaccines, we
found that V2-SET immunogens induced broader and more potent tier 2 heterologous NAbs in guinea pigs than
wild-type Envs, indicating that inclusion of bNAb signatures significantly improved vaccine performance (2).
Studying 20 novel SHIVs in ~100 rhesus macaques (RMs) (3), we found that ~15% of animals developed varying
degrees of heterologous breadth by 6-24 months, with the most common bNAb specificity targeting the V2 apex
(Table 1). However, bNAb induction in SHIV infection is still infrequent, thus providing a unique experimental
setting to test iterative Env design improvements in a manner that is faster and less costly than human trials.
Our hypothesis is that by (i) minimizing distracting glycan hole epitopes, (ii) increasing Env affinity for V2 apex
bNAb precursors, (iii) increasing relevant epitope diversity in vaccine boosts, and (iv) incorporating B cell lineage
immunogen designs, we will improve V2 bNAb germline engagement and bNAb lineage maturation. We have
selected the CRF.AG.T250 (T250) and CAP256SU (CAP256) Envs as baseline immunogens, because both
have generated V2 apex bNAbs in SHIV infected RMs (Table 1). In Aim #1, we will optimize the Env glycan
shield and V2 germline targeting properties of T250 and CAP256 Envs, test their replication potential and tier 2
antigenicity in SHIV vectors, and down-select the best performing set for subsequent infection of RMs. In Aim
#2, we will compare the bNAb induction capacity of SHIVs expressing wildtype (WT), glycan-optimized (GLY-
OPT), and glycan and germline-optimized (GLY/UCA-OPT) versions of the same Env in RMs and determine the
envelope-antibody (Env-Ab) coevolution pathways in all animals that develop neutralization breadth. In Aim #3,
we will rationally design new V2 apex directed immunogens using Env-Ab co-evolution data and the V2-SET
strategy as a guide, and deliver them using nucleoside-modified mRNA containing lipid nanoparticles
(mRNA/LNPs) that express stabilized, membrane bound gp160s. We will prime RMs with the best performing
Env from Aim #2, and then compare the bNAb induction capacity of this Env with that of two boosting regimens
specifically designed to increase relevant epitope diversity. Immunized RMs will receive a low-dose repetitive
rectal SHIV challenge to assess their level of protection as recently described (4) and to study their breakthrough
infections. By simultaneously applying multiple vaccine improvement strategies, we expect to improve V2 apex
bNAb induction in RMs and translate these findings into more effective vaccines for humans.
Terms: <AIDS Vaccines><AIDS vaccine><Affinity><Amino Acids><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><Antibody Specificity><Antigenic Determinants><Antigens><Autologous><Avidity><B blood cells><B cell><B cell receptor><B cells><B-Cell Receptor Binding><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CDR3-region><Cavia><Cell Lineage><Clinical Treatment Moab><Complement><Complement Proteins><Complementarity Determining Region 3><Complementarity Determining Region III><Country><Data><Development><Dose><Epitopes><Event><Evolution><Frequencies><Glycans><Goals><Guinea Pigs><Guinea Pigs Mammals><HIV vaccine><HIV-1><HIV-1 vaccine><HIV-I><HIV/AIDS Vaccines><HIV1><HIV1 vaccine><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Immunize><Infection><M mulatta><M. mulatta><Macaca mulatta><Maps><Masks><Membrane><Messenger RNA><Modern Man><Molecular Interaction><Monkeys><Monoclonal Antibodies><Nucleosides><Pathway interactions><Pattern><Performance><Phase><Polysaccharides><Prevalence><Property><Public Health><Receptors, Antigen, B-Cell><Regimen><Resistance><Rhesus><Rhesus Macaque><Rhesus Monkey><SHIV><T4 Cells><T4 Lymphocytes><Testing><Translating><Vaccinated><Vaccination><Vaccine Design><Vaccine Research><Vaccines><Variant><Variation><aminoacid><base><bio-informatics tool><bioinformatics tool><complementarity-determining region 3><cost><design><designing><developmental><human immunodeficiency virus vaccine><immunogen><improved><in vivo><lipid nanoparticle><mAbs><mRNA><membrane structure><model of animal><model organism><neutralizing antibody><neutralizing mAb><neutralizing monoclonal antibodies><new vaccines><next generation vaccines><novel><novel vaccines><pathway><rectal><resistant><response><simian HIV><simian human immunodeficiency virus><third complementarity-determining region><tissue culture><vaccine delivery><vaccine efficacy><vector><virtual>