CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

fused to HIV-1 Envelope (LC.Env), inducing antigen-specific humoral responses in mice and human LC:T/B co-cultures. In this study, we aimed to refine LC targeting by designing three Env monochains instead of 2 (LC3.Env3) mimicking natural Env conformation. We aim to investigate whether these new trimeric Env constructs could stimulate germinal center (GC) and Tfh cell reactions, ultimately leading to the production of Env-binding IgG and HIV neutralizing antibodies (NeutAb) in vivo. Methods: B6 mice were intradermally immunized with LC3.Env3 or control LC.Env mAb (5 mcg of Env antigen) at day (D) 0 and D21, without adjuvant. Antibody (magnitude and affinity) and cellular responses were assessed post-prime (PP) and post-boost (PB) using Luminex and FACS, respectively. GC/Tfh reactions in draining lymph nodes (dLN) were monitored through immunofluorescence at various times. Additionally, rabbits were subcutaneously immunized with 50 mcg LC3.Env3 without adjuvants, and serum NeutAb levels were evaluated. Results: Compared to LC.Env, LC3.Env3: (i) elicited a rapid and potent Env-IgG response, with mean titers measuring 22- and 37-fold higher at D14 PP and D7 PB, respectively. (ii) enhanced the avidity of anti-Env IgG, resulting in an index increase of 12% and 36% at D14 PP and D7 PB, respectively. This was accompanied by a marked expansion of Tfh and GC B cells (GL-7+/Fas+) at D7 PB. (iii) swiftly induced the formation of structured germinal centers in dLN, indicative of a robust immune response. Significant Tier-1 NeutAb induction was observed in rabbits immunized with LC3.Env3. Conclusion: This study underscores that HIV Env antigen can be adeptly targeted to LC as a trimer, intensifying both the magnitude and quality of humoral responses without using any adjuvant and after only two shots. In addition, the strategy of targeting SOSIP-like trimeric Env to LC holds substantial promise for eliciting broadly neutralizing antibodies (bNAb) against HIV and will require an optimization of the vaccination regimen. Mucosal HIV Vaccine Targeting Host Epithelial Stem Cells for Long-Term Immunity Robert White 1 , Vida Hodara 1 , Patrice Frost 2 , Pamela A. Kozlowski 3 , Francois J. Villinger 4 , Marie- Claire Gauduin 1 1 Texas Biomedical Research Institute, San Antonio, TX, USA, 2 Southwest National Primate Research Center, San Antonio, TX, USA, 3 Louisiana State University, New Orleans, LA, USA, 4 University of Louisiana at Lafayette, Lafayette, LA, USA Background: HIV transmission occurs predominantly across mucosal surfaces; an ideal vaccine should be to target HIV at mucosal entry sites to prevent infection. We developed a SIV single-cycle replication- deficient vaccine under the control of the involucrin promoter, which was tested for its ability to drive SIV expression in terminally differentiated epithelial cells, induce mucosal immune responses, offering protection against SIV. Methods: Sixteen macaques (8 females, 8 males) were immunized (1 dose: 50ng p27=3x10 11 RNA copies, atraumatic, needleless) at week 0 and monitored over time for specific immune responses in blood, mucosal secretions, and various lymphoid/non-lymphoid tissues. At weeks 12 (group 1) or 24 (group 2), animals were challenged with repeated low-doses SIVmac239 (intravaginal, 2500 TCID 50 /ml; intrarectal at 300 TCID 50 /ml) 4 females and 4 males per group. Sixteen additional animals (8 females, 8 males) served as unvaccinated SIV infected Controls. Results: Within two weeks post-vaccine, strong mucosal antibody responses (IgG, IgA) and specific CD8+ T-cells were detected. Immunohistofluorescence revealed antigens-expression in epithelia upper-layers. SIVenv was detected via anti-gp120 immunoPET/CT scans in female vagina and draining-LN as well as in male rectal and transversal. SIV-challenges demonstrated a significant delay and/or lower viremia (2-3 logs-reduction, peak; 4-5 logs-reduction, set-point) to undetectable viremia 10-20 weeks post-SIV in vaccinees. Robust SIV- specific T-cell responses were also detected in blood, lymph-nodes, and mucosa tissues. Controls had high viremia (log 10 : 7.2-8.7 viral-RNA copies/ml, peak) and significant gut CD4+ T-cells depletion. We demonstrated a positive correlation between mucosal and systemic T-cell responses and control of viremia, and inverse associations between viremia and post-challenge vaginal antibody responses. All vaccinees manifested durable aviremic SIV-control for 2 years when CD8-depletion was performed. The dramatic fall in viremia coincided with the CD8+ T-cells recovery and significant increase of SIV-specific responses. Conclusion: The study demonstrated the efficacy of an epithelial stem cell based vaccine to serve as antigen delivery to generate specific mucosal antibody

elicited functional antibody responses, including binding antibody multiplex assay (BAMA), antibody- dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP) assays, were measured by HVTN core labs. Pearson correlation analysis of IgG and FcR genetic variants was used to identify potential linkage disequilibrium (LD). Relationships between genotypes and antibody responses were identified by linear regression controlling for treatment group and region. Variants were deemed to be associated with antibody responses when the p-value was below 0.05 and the Benjamin Hochberg false discovery rate (FDR) adjusted value below 0.2. Results: In the study population, there was evidence of LD within IgG and FcR alleles, but no strong correlations between specific IgG and FcR alleles (all r values were <0.5). The distribution of many polymorphisms significantly differed between the US and South Africa. Within the subset of the cohort tested for functional antibody responses (IgG, n=41; FcR, n=55), we determined that IgG genotypes such as IgG1_12 (p=0.010, p=0.027), IgG3_11 (p=0.028, p=0.050), IgG2_02 (p=0.032, p=0.102), IgG4_07 (p=0.064, p=0.133), and others were associated with vaccine-elicited ADCC antibody titers and activity peaks when corrected for vaccine group and regional effects. In the same way, we identified that the FCER1A rs2427827 had a significant association with higher peak ADCC activity and the FCGR2A rs1801274 mutation was associated with a higher antibody binding to a subtype C V1V2 antigen. Conclusion: Multiple IgG genotypes and FcR mutations were associated with ADCC and binding antibody levels after HVTN108 vaccination when controlling treatment and region. Genetic variation in both antibodies and FcRs contributes to vaccine-induced humoral responses but there were significant regional differences in their distribution, suggesting regional development of HIV vaccines may be scientifically appropriate. Developing Novel HIV-1 Env Proteins That Efficiently Engage the Unmutated Forms of VRC01-Class Abs Parul Agrawal , Junli Feng, Arineh Khechaduri, Kelsey R. Salladay, Latha S. Kallur, Madison M. Means, Matthew D. Gray, Leonidas Stamatatos Fred Hutchinson Cancer Center, Seattle, WA, USA Background: VRC01-class antibodies are potent and broadly neutralizing antibodies (bnAbs) that protect animals from experimental S/HIV infection and have been shown to prevent HIV-1 acquisition in two phase 3 clinical trials. These antibodies target the CD4 binding site (CD4-BS) of the HIV-1 envelope glycoprotein (Env), but their predicted germline (gl) forms bind the Envs inefficiently. This is potentially why Env immunization has so far failed to elicit VRC01-class antibodies. We previously reported that specific modification of the clade C Env 426c lead to its binding by several glVRC01-class Abs. Methods: Based on new structural information of Envs, we have now identified additional N-linked glycosylation site mutations that allow Envs from different clades to bind glVRC01-class antibodies (Biolayer Interferometry assays, BLI) and to activate B cells engineered to express glVRC01-class B cell receptors (Ca2+ flux assays) in vitro; and also activate the corresponding B cells in vivo when used as prime immunogens in knock-in mice expressing human VRC01 class B cell receptors. Results: Importantly, our current studies suggest that although different gl-targeting Envs can engage glVRC01 B cells; because of differences in VRC01 epitope exposure on these gl-targeting Envs, different VRC01-cass antibodies are elicited by the different gl-targeting Envs. Conclusion: These findings are central to efforts to engage a broad spectrum of VRC01-class precursors in clinical trials. Enhancing HIV Vaccine Efficacy via Langerhans Cell-Targeted Env Trimers Adele Hammoudi 1 , Mathieu Surenaud 1 , Florence Picard 1 , Jade Legros 1 , Emma Sicherre 1 , Borys Pedenko 2 , Christiane Moog 3 , Winfried Weissenhorn 4 , Mireille Centlivre 1 , Véronique Godot 1 , Yves Levy 1 , Sylvain Cardinaud 1 1 Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France, 2 Institut de Biologie Structurale, Grenoble, France, 3 University of Strasbourg, Strasbourg, France, 4 Grenoble Alpes University, Grenoble, France Background: Developing an effective HIV-1 vaccine is contingent on generating protective antibodies (Abs). Novel antigen delivery methods are needed to enhance immune responses. One promising approach involves directing antigens to dendritic cells (DC) through fused monoclonal antibodies (mAbs) to amplify both cellular and humoral responses. Previous studies have shown success in targeting skin Langerhans cells (LC) with anti- Langerin mAbs

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CROI 2024