CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

after the third injection. Secondary endpoints included changes in CD4 count, CD4/CD8 ratio and inflammation markers. A post-hoc analysis, categorized patients in 3 groups according to anti-3S Ab response: non-responders (NR: < 4-fold increase), low-responders (LR: between 4 and 10-fold increase), and high-responders (HR: ≥10 fold-increase). Results: At baseline (mean values), patients were mostly males (79.1%), age: 47 yrs, ART duration: 13.65 yrs, CD4 cells: 365.2, CD4/CD8: 0.7075. The proportion of responders versus placebo was 45.8% (p=0.0026), 62.5% (p=0.0002) and 47.8% (p=0.0020) in the 16, 32 and 64 µg groups, respectively. No statistical differences were observed in secondary endpoints. In post-hoc analysis, 20 patients were HR, 16 LR and 50 NR. CD4 nadir, age, HIV duration did not impact anti-3S response except for CD4/CD8 ratio (p=0.0069). At week 48, a significant increase in CD4 count (+ 60 CD4/mm 3 ; p=0.0029) was observed in patients with anti-3S Ab >100 AU, compared to baseline. Anti-3S responses were significantly correlated with CD4 increase in all vaccinated patients (p=0.002). One viral rebound was observed after ART discontinuation. VAC-3S was well tolerated with no SAEs and no systemic AEs leading to premature discontinuation; 69% of patients experienced mild local reactions. Conclusion: VAC-3S was safe and induced a significant Ab response, higher in patients with higher CD4/CD8 ratio at baseline. An increase in CD4 count was observed in patients with higher Ab rate.

the vaccination. Patients who received the highest dose showed a moderate increase in T cell responses spanning HTI sequence (IN) at w8 whereas no changes were observed in responses against the rest of the HIV-1 proteome (OUT). In addition, the proportion of responders receiving any dose of iHIVARNA (n= 15) increased from 31% at w0 to 80% post-vaccination. This increase was not observed in patients receiving TriMix alone (n=6, from 50% to 67%). Vaccination did no impact on caHIV-DNA levels in any of the studied arms. However, caHIV-RNA expression and usVL were transiently increased in patients receiving the higher doses of iHIVARNA at w5 and 6. We did not observe differentially expressed genes in any of the groups-wise comparisons, although gene set analysis indicates slight effects on pathways such as RNA metabolism and host response to viruses. Conclusion: This phase I exploratory dose-escalating trial showed that iHIVARNA was safe and well tolerated, was able to induce moderate HIV-specific immune responses and transiently increased caHIV-RNA expression. These data support further exploration of iHIVARNA in the ongoing phase II study. 312 HIV ANTIBODY GLYCOFORMS MODULATE IMMUNE COMPLEX-DRIVEN INNATE AND ADAPTIVE IMMUNITY Giuseppe Lofano 1 , Wen-Han Yu 1 , Margaret Ackerman 2 , Todd J. Suscovich 1 , Galit Alter 1 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 Dartmouth College, Hanover, NH, USA Background: HIV broadly neutralizing antibodies (bNAbs) confer protection following passive immunization, but the immunological mechanisms that drive their development in a fraction of HIV infected individuals are poorly understood. Structural features of bNAbs indicate that they originate from extensive B cell germinal center reactions, which rely on immune complex (IC)- mediated delivery of antigen to follicular dendritic cells (FDCs). However, little is known about the role of immune complexes in tuning the evolution of bNAbs. Methods: Here we characterized the HIV-specific antibody responses in a group of Neutralizers that neutralized 80% of 11 tier 2 viruses, and a matched group of Non-Neutralizers that exhibited no detectable neutralizing activity. Firstly, we applied a system serology Fc-profiling platform to determine Fc structural features that are associated with the development of Fab neutralizing activity. Then, we developed a new series of Fc-engineered immune complexes- based adjuvants and characterized their mechanisms of action in mouse vaccination studies. Results: We show that HIV-specific antibodies from Neutralizers mediate better antigen phagocytosis and complement deposition, bind better Fc-receptors and complement proteins, and are associated with increased functionality in mouse vaccination studies (Fig.1A). We than hypothesized that such functional differences were determined by structural modifications of the HIV-specific antibodies. Biophysical characterization of the antibody Fc of HIV- specific antibodies revealed that sialylated IgG1 antibodies were associated with the development of bNAbs (Fig.1B). Given the importance of antigen-antibody immune complexes in driving antibody Fab maturation, we rationally designed immune complex-based vaccines with IgG1 antibody glycoforms to use in mouse vaccination studies. Finally we show that sialylated IgG1 antibodies, in immune complexes with HIV gp120, work as adjuvants to promote enhanced antigen uptake from innate immune cells, expanded germinal centers and increase HIV-specific humoral responses as compared to non-sialylated IgG1 antibodies (Fig.1C-D). Conclusion: This work supports a potentially critical adjuvanting role for specific glycosylated IC forms in promoting more effective B cell selection that may contribute to the rational design of neutralizing antibody-inducing vaccines against HIV.

Poster Abstracts

311 PHASE I CLINICAL TRIAL OF AN MRNA-BASED THERAPEUTIC VACCINE AGAINST HIV-1 INFECTION Lorna Leal 1 , Alberto C. Guardo 2 , Sara Moron-Lopez 3 , Maria Salgado 3 , Beatriz Mothe 3 , Carlo Heirman 4 , Kris Thielemans 4 , Pieter Pannus 5 , Christian Brander 3 , Rob Gruters 6 , Arno Andeweg 6 , Javier Martinez-Picado 3 , Montserrat Plana 2 , Felipe Garcia 1 1 Hospital Clinic of Barcelona, Barcelona, Spain, 2 IDIBAPS, Barcelona, Spain, 3 IrsiCaixa Institute for AIDS Research, Badalona, Spain, 4 Vrije Universiteit Brussel, Brussels, Belgium, 5 Institute of Tropical Medicine, Antwerp, Belgium, 6 Erasmus University Medical Center, Rotterdam, Netherlands Background: The efficacy of therapeutic vaccines has been modest. The combination of new vectors targeting dendritic cells (DC) pathways and new antigenic sequences to redirect responses toward target unmutated epitopes could be necessary to achieve the remission of HIV-1 infection. We performed the first-in-human clinical trial with naked mRNA (iHIVARNA) encoding DC activation signals (TriMix:CD40L+CD70+caTLRA4) combined with HIV antigenic sequences (HTI sequence:comprising 16 joined fragments from Gag, Pol, Vif and Nef) rationally selected to redirect the responses to the most vulnerable viral targets. Methods: A dose scalating phase I clinical trial was performed in 21 chronic HIV-1 infected patients who received 3 intranodal doses of mRNA at weeks 0, 2 and 4 as follow: TriMix 100mg (n=3), TriMix 300mg (n=3), TriMix 300mg+HTI 300mg (n=3), TriMix 300 mg+HTI 600mg (n=6), TriMix 300 mg+HTI 900mg (n=6). Primary end-point was safety and secondary-exploratory end-points were immunogenicity (ELISPOT), changes in reservoir (caHIV-DNA and caHIV- RNA), ultrasensitive plasma RNA (usVL) and transcriptome (limma). Results: Overall, the vaccine was safe and well tolerated. No serious adverse events (AEs) were observed. There were 31 grade 1/2 and 1 grade 3 AEs, fromwhich half of grade 1/2 and the grade 3 were definitely not related to

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