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This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice
related to any specific patient.
Frontier AIDS Education and Training Center
CROI 2016 Review: Immunology and Vaccines
Meena Ramchandani MD MPH
Acting Instructor, University of Washington
March 2016
Abstract 32LB
ACTG 5340:THE EFFECT OF VRC01 ON VIRAL KINETICS AFTER
ANALYTIC TREATMENT INTERRUPTION
Antibodies
Vaccines
Improved potency and breadth
Prevention
1. Prevent the acquisition of infection
- Block a transmission event
Treatment
1. Complementary to ARVs
2. Potential to impact the cell-associated viral reservoir
- Block Viral Entry
- Cell Killing
CD4 T cell
(Kong et al. J Virol 2015)
Katharine Bar. CROI 2016. Boston
ACTG 5340:The Effect of VRC01 on Viral Kinetics
After Analytic Treatment Interruption
Vaccines
• 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)
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)
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/mm3 (470-1,586)
Nadir CD4 count >200
Median time on ART 4.7 years (2.7-14.5)
ART regimen 71% on INSTI, 29% on PI regimen
Study Design
Vaccines
• 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
Katharine Bar. CROI 2016. Boston
Study Design
Viral Rebound
Katharine Bar. CROI 2016. Boston
Time to Viral Rebound
Vaccines
38% vs 13% suppression at 4
weeks , p=0.04
8% vs 3% suppression at 8
weeks, p=0.44
Conclusions
Vaccines
• 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
Neutralizing Antibodies: Plans for Clinical Trials
Vaccines
Richard A Koup. Immunology and Vaccines. CROI 2016. Boston.
Richard A Koup. Immunology and Vaccines. CROI 2016. Boston.
Future: Bifunctional Antibodies (bind HIV and
CD3/CD8), Combining Antibodies, Longer Acting
Vaccines
BITE:
Bispecific T cell engager
Infected
CD4 T-cell
CD3+CD8+
T-cell
T cell
HIV infected
target cell
DART:
Dual affinity re-targeting
protein
Abstract 21
HYPERACUTE MICROBIAL TRANSLOCATION DURING PATHOGENIC SIV
INFECTION
Adam Ericsen, et al. CROI 2016. Boston
The Microbiome
Immunology
• Affects everything
• >104 bacteria on the human body
• >1,000 species
• Gut microbiome: changes over time
• Age
• Food
• Obesity
• Malnutrition
• Antibiotic treatment
• Among others….
Richard A Koup. Immunology and Vaccines. CROI 2016. Boston.
The Microbiome and HIV
Immunology
• 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 2015.
Adam Ericsen, et al. CROI 2016. Boston
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 2016. Boston
Study Design
Immunology
Same:
diet, immunizations, antibiotics
-42 0 8 14 18 21 -42 56
Days post infection
SIV intrarectal
1. Blood: T cell activation (FACS)
2. Blood: Plasma analytes (ELISA)
3. Blood: 16S rDNA sequencing/qPCR
4. Stool: 16S rDNA sequencing
Adam Ericsen, et al. CROI 2016. Boston
Results
Adam Ericsen, et al. CROI 2016. Boston
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 re-
activation
• Other topics:
• Distinct gut microbiota composition in gay men
• HIV changes in gut and disease progression
• Immune modulation
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
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)
