CROI 2016 Review: Immunology and Vaccines

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1 Frontier AIDS Education and Training Center CROI 2016 Review: Immunology and Vaccines Meena Ramchandani MD MPH Acting Instructor, University of Washington March 2016 This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice related to any specific patient.

2 ACTG 5340:THE EFFECT OF VRC01 ON VIRAL KINETICS AFTER ANALYTIC TREATMENT INTERRUPTION Abstract 32LB

3 Vaccines Antibodies Prevention 1. Prevent the acquisition of infection - Block a transmission event Treatment 1. Complementary to ARVs 2. Potential to impact the cellassociated viral reservoir - Block Viral Entry - Cell Killing CD4 T cell Improved potency and breadth (Kong et al. J Virol 2015)

4 Vaccines ACTG 5340:The Effect of VRC01 on Viral Kinetics After Analytic Treatment Interruption VRC01 is a monoclonal antibody (mab) Broadly neutralizing (bnabs) Directed at the CD4 binding site of HIV-1 Env Neutralizes most HIV isolates Protected simians from retroviral changes Objective: to evaluate whether high dose passive administration of VRC01 can prevent or delay the return of viremia after ART interruption Goals: open label study, suppressed HIV-1 infected individuals Monitored treatment interruption (ATI) Katharine Bar. CROI Boston

5 ACTG 5340:The Effect of VRC01 on Viral Kinetics After Analytic Treatment Interruption Goals: open label study, suppressed HIV-1 infected individuals Safe and tolerable Maintains high levels of plasma VRC01 Delays or prevents viral rebound Monitored treatment interruption (ATI)

6 Vaccines Study Design VRC01 40 mg/kg by IV infusion Q3 weeks 3 doses All participants on PI or INSTI based ART regimen ART restarted after confirmed HIV RNA >200 c/ml Characteristics Number of Participants 14 (13 evaluated, 1 stopped ART) Sex/Age 100% male, Median age 38 (27-52) Race 50% African American, 50% Caucasion, 14% Latino Mean CD4 count 896 c/mm 3 (470-1,586) Nadir CD4 count >200 Median time on ART 4.7 years ( ) ART regimen 71% on INSTI, 29% on PI regimen

7 Katharine Bar. CROI Boston Study Design

8 Viral Rebound

9 Vaccines Time to Viral Rebound 38% vs 13% suppression at 4 weeks, p=0.04 8% vs 3% suppression at 8 weeks, p=0.44 Katharine Bar. CROI Boston

10 Vaccines Conclusions Passive immunization with high doses of a single bnab (VRC01) failed to prevent rebound viremia in the majority of participants Rebound was delayed when compared to historical controls. Two participants maintained suppression for 7 and 10 weeks in the absence of any other ART. Phase IIB efficacy study planned: HPTN and HVTN Can prevent HIV infection in humans? Cohorts MSM in NA and SA, women in Africa Open in 2016

11 Vaccines Neutralizing Antibodies: Plans for Clinical Trials Richard A Koup. Immunology and Vaccines. CROI Boston.

12 Vaccines Future: Bifunctional Antibodies (bind HIV and CD3/CD8), Combining Antibodies, Longer Acting Infected CD4 T-cell HIV infected target cell CD3+CD8+ T-cell T cell BITE: Bispecific T cell engager DART: Dual affinity re-targeting protein Richard A Koup. Immunology and Vaccines. CROI Boston.

13 HYPERACUTE MICROBIAL TRANSLOCATION DURING PATHOGENIC SIV INFECTION Abstract 21

14 Immunology The Microbiome Affects everything >10 4 bacteria on the human body >1,000 species Gut microbiome: changes over time Age Food Obesity Malnutrition Antibiotic treatment Among others. Adam Ericsen, et al. CROI Boston

15 Immunology The Microbiome and HIV Microbial translocation immune activation Focal structural barrier damages cause microbial translocation and immune activation in SIV infected monkeys Estes, et al. Plos Pathogens 2010 Dysbiosis in HIV infected individuals: change in microbiome Dillon et al. Mucosal Immunology 2014 Vujkovic-Cvijin et al. Science Translational Medicine 2014 Probiotics reduce lymphoid follicle fibrosis SIV infected monkeys on ART Klatt et al. JCI 2013 Reason for decreased response to HVTN 505 Wilton B Williams et al. Science Richard A Koup. Immunology and Vaccines. CROI Boston.

16 Hyperacute Microbial Translocation During Pathogenic SIV Infection What s driving acute viremia? SIV infected cynomolgus macaques Performed 16S ribosome deep sequencing and quantitative PCR Investigate SIV associated alteration to the composition and abundance of microbial products within stool and blood plasma Does microbial translocation occur during acute HIV infection Does this drive early viral replication Evaluating gut microbial community during acute phase Will this influence controllers from progressers Adam Ericsen, et al. CROI Boston

17 Immunology Study Design SIV intrarectal 1. Blood: T cell activation (FACS) 2. Blood: Plasma analytes (ELISA) 3. Blood: 16S rdna sequencing/qpcr 4. Stool: 16S rdna sequencing Same: diet, immunizations, antibiotics Days post infection Adam Ericsen, et al. CROI Boston

18 Adam Ericsen, et al. CROI Boston Results

19 Conclusion Prior to peak SIV viremia High magnitude influx of microbial DNA into the peripheral blood See intestinal permeability Reduction of LPS specific antibodies and soluble CD14 levels (not significant) Increase in peripheral CD4+CCR5+ cells (frequency and abs count between day 0 and 8 p=0.008) Implications for prophylactic vaccination and reservoir reactivation Other topics: Distinct gut microbiota composition in gay men HIV changes in gut and disease progression Immune modulation Adam Ericsen, et al. CROI Boston

20 Take Home Points Neutralizing antibodies: long acting Potential for both treatment and prevention Next generation mab: more potent and breadth Options for genetic immunization Guide vaccine field and knowledge of HIV Microbiome Important possible effect of immune modulation Might influence hyperacute HIV infection and viremia

21 Other Interesting Abstracts 1. Single dose zoledronic acid prevents antiretroviral Induced Bone loss (Ighovwerha Ofotokun Emory University School of Medicine, Atlanta, GA, United States) 2. Comparing Cardiovascular Disease Risk Scores for Use in HIV-Infected Individuals (Heidi M. Crane1 University of Washington, Seattle, WA, United States) 3. Early Antiretroviral Therapy Does Not Improve Vascular Function: A START Substudy (Jason V. Baker, Hennepin County Medical Center, University of Minnesota, Minneapolis, MN, United States)