356 - Molecular signatures at baseline and post-vaccine predict humoral immunogenicity of a GLA-SE adjuvanted gp120 HIV vaccine in infants.

Publication Number: 2345.356

Kinga K. Smolen, Boston Children's Hospital, Boston, MA, United States; Joann Diray-Arce, Boston Children's Hospital, Boston, MA, United States; Annmarie Hoch, Boston Children's Hospital, Cambridge, MA, United States; Thomas Kouyate, Boston Children's Hospital, Boston, MA, United States; Caitlin Syphurs, Boston Children's Hospital, Boston, MA, United States; Jing Chen, Boston Children's Hospital, Boston, MA, United States; Dylan Nicholas Tabang, Boston Children’s Hospital & Harvard Medical School, Boston, MA, United States; Athena Nguyen, Boston Children's Hospital, Washington, DC, United States; Alec Plotkin, Boston Children's Hospital, Morrisville, NC, United States; Jensen Pak, Boston Children's Hospital, Boston, MA, United States; Asimenia Angelidou, Harvard Medical School, Boston, MA, United States; Al Ozonoff, Harvard Medical School, Boston, MA, United States; Tobias R. Kollmann, Dalhousie University, Halifax, NS, Canada; Scott Tebbutt, UBC, Vancouver, BC, Canada; William Hahn, University of Washington, Seattle, Seattle, WA, United States; Holly Janes, Fred Hutchinson Cancer Center, Seattle, WA, United States; Troy M. Martin, Fred Hutch Cancer Center, Seattle, WA, United States; David Martino, The Kids Research Institute Australia, Perth, Western Australia, Australia; Hanno Steen, Boston Children's Hospital, Boston, MA, United States; Ofer Levy, Precision Vaccines Program, Boston Children's Hospital, Boston, MA, United States

Background: Despite remarkable progress in HIV treatment and prevention, >1.5 million children continue to live with HIV globally, with the majority acquiring the infection perinatally or during breastfeeding. A pediatric HIV vaccine inducing durable protective immunity could transform prevention efforts in high-burden settings. Yet, most HIV vaccine research has focused on adults, and the unique features of the developing infant immune system remain underexplored in vaccine design and evaluation.

Objective: To understand pre- and post-vaccine molecular signatures that associate with humoral immunogenicity response of the GLA-SE adjuvanted HIV vaccine in infants using multi-omic systems vaccinology approaches.

Design/Methods: The HIV Vaccine Trials Network (HVTN) 135 study was a phase I randomized, placebo-controlled trial of glucopyranosyl lipid A-stable emulsion (GLA-SE) adjuvanted CH505 transmitter-founder (CH505TF) gp120 immunogen vaccine (NCT04607408). Healthy HIV-negative infants, born to women living with HIV, were randomized to 5 doses of placebo (N = 10) or CH505TF plus GLA-SE-adjuvanted gp120 (N = 28). Blood was collected at pre- and post-vaccine timepoints (including Day (D)1 of study and 14 days post dose 1 (D14), 14 days post dose 2 (D70), and 14 days post dose 3 (D126)) and fractionated using a ‘small sample to BIG DATA’ workflow for extracting epigenetic, transcriptomic, proteomic, metabolomic, cytokine and chemokine measurements.

Results: Bioinformatic-indexed analysis of later to earlier timepoints revealed expected dynamic molecular ontogenetic changes across the first months of life. Longitudinal profiling revealed that compared to placebo, the vaccine induced significant transcriptomics changes one day after the first vaccine dose, with 143 pathways significantly upregulated (including interleukins signaling, MyD88 cascade, and neutrophil degranulation) and 74 pathways significantly downregulated (including translation, rRNA processing, and viral mRNA translation). Distinct plasma cytokine and chemokine signatures at baseline (enhanced IL6, TNFβ, IL18) and D14 post vaccine (attenuated IL1β, IL13, CX3CL1, CCL7, IL12p40, IL15, IL12p70), are associated with induction of Tier 1 neutralizing antibody ID50 titers to CH505.w4.3 virus.

Conclusion(s): Overall, preliminary analysis of the HVTN135 study demonstrates feasibility of multi-omic systems vaccinology in early life enabling integration of clinical, immunologic, and systems biology data. Molecular signatures predicting immunogenicity of GLA-SE adjuvanted gp120 vaccine can inform future infant HIV vaccine discovery and development.