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Provides basic scientific knowledge on a range
of HIV cure research related topics
Strengthens community capacity to
participate in and make decisions about HIV
cure research
Promotes the ethical development and
implementation of HIV cure clinical studies
THERAPEUTIC VACCINES AND
IMMUNE-BASED THERAPIES
HIV Cure Research Training Curriculum
Richard Jefferys, Treatment Action Group
Jeffrey Jacobson, Drexel University
May 2015
The HIV CURE training curriculum is a collaborative project aimed at making HIV
cure research science accessible to the community and the HIV research field.
Table of Contents
Therapeutic Vaccines
Passive immunization
Adoptive immunotherapy
Immune-based therapies (IBTs)
Future directions and challenges
Therapeutic vaccination
•
•
Rationale: strengthen or create new and
more effective immune responses to HIV in
HIV-positive individuals
Challenging because CD4 T cells normally
play a central role in coordinating the
immune response to infection
• CD4 T cells are the primary target of HIV and are
disrupted and killed by the virus
• CD4 T cells targeting HIV (HIV-specific CD4 T
cells) are preferentially infected
Types of immune response
•
Innate immunity
• Consists of non-specific responses to pathogens
based on shared features
• Transient activity
•
Adaptive immunity
• Specifically recognizes pathogen fragments
(antigens)
• CD4 T cells, CD8 T cells, B cells (produce
antibodies), natural killer cells (possibly)
• Responses persist as “memory” cells
Therapeutic vaccination
•
•
•
•
Generate long-lived adaptive immune
responses targeting HIV antigens
Induction of innate immunity can help
generate adaptive immune responses (e.g.
via vaccine adjuvants)
Focus has been on CD4 T cell and CD8 T cell
responses (cellular immunity)
Increasing interest in B cells due to potential
to produce antibodies that can flag virusinfected cells for destruction
Therapeutic vaccines
•
•
•
Use various methods to deliver noninfectious HIV antigens into the body (most
often injection into muscle tissue)
Antigens are picked up and processed by
immune system sentinels called antigenpresenting cells (dendritic cells and
macrophages)
Antigens then presented to CD4 T cells, CD8
T cells and B cells, inducing immune
responses
Types of therapeutic vaccines
•
DNA and RNA vaccines
• Consist simply of genetic code for HIV antigens
•
Viral vector vaccines
• Genetic code for HIV antigens inserted into modified
non-pathogenic virus e.g. canarypox (ALVAC), modified
Vaccinia Ankara strain (MVA), adenoviruses, lentiviruses
•
Protein or peptide vaccines
• Mimics of HIV proteins or protein fragments (peptides)
•
Dendritic cell vaccines
• Extract antigen-presenting dendritic cells, mix with HIV
antigens outside the body (sometimes HIV antigens
derived from individual’s virus), then injected as vaccine
Therapeutic vaccine studies
•
•
So far, mostly studied in people on
antiretroviral therapy (ART) (some
exceptions) with impact on viral load
measured after ART interruption
A few studies have reported significant
reductions in viral load associated with
therapeutic vaccination, albeit typically
transient
Fig. 2 Change in pVL from baseline (before any antiretroviral therapy) after immunizations
and second interruption of antiretroviral therapy.
Felipe García et al., Sci Transl Med 2013;5:166ra2
Published by AAAS
Therapeutic vaccines in cure research
•
•
•
Goal for therapeutic vaccination has largely
shifted to elimination of latent HIV reservoir
Therapeutic vaccines are being combined
with latency-reversing agents (LRAs)
The rationale:
• LRA triggers latent HIV to produce viral proteins
• HIV antigens are expressed by infected cell
• Immune responses induced by therapeutic
vaccine recognize HIV antigens and kill infected
cell (T cells) or flag for destruction (antibodies)
Therapeutic vaccines in cure research
Stephen A. Migueles and Mark Connors. Small Molecules and Big Killers: The Challenge of Eliminating the Latent HIV
Reservoir, Cell, Volume 36, Issue 3, p320–321, 23 March 2012
Therapeutic vaccine trials
2015
ChAdV63.HIVcons
+ MVA.HIVconsv
2016
AGS-004
Vac-3s
2017
2018
GTU-MultiHIV
+ LIPO-5
GTU®-MultiHIV
B Clade Vaccine
Vac-3s
Tat-Oyi
RIVER:
ChAdV63.HIVconsv
+ MVA.HIVconsv
vaccines, vorinostat
Vacc-4x +
romidepsin
THV01
HIVAX
IHIVARNA-01
MAG-pDNA +
rVSVIN HIV-1 Gag
http://www.treatmentactiongroup.org/cure/trials
Therapeutic vaccines in cure research
Ongoing trial in Denmark is combining the LRA
romidepsin (an HDAC inhibitor) with the
therapeutic vaccine Vacc-4x (consisting of HIV
peptides)
• Planned UK trial named RIVER aims to combine
an LRA with two viral vector-based therapeutic
HIV vaccines (chimpanzee adenovirus & MVA)
• Planned US CARE collaboratory trial will
combine an LRA with a dendritic cell-based
therapeutic HIV vaccine (AGS-004)
•
Unconventional therapeutic vaccines
•
VAC-3S aims to prevent CD4 T cell depletion by
inducing antibodies to block a mechanism believed
to be involved in triggering immune activation and
CD4 T cell death (as opposed to targeting HIV
directly)
• Ongoing trials
•
Vacc-C5 also aims to induce antibodies that may
block immune activation
• Trial completed, results pending
•
A vaccine that suppresses immune responses to SIV
has been reported to protect macaques from
infection and suggested to have therapeutic
potential
• Clinical trial planned, possible launch toward end of 2015
Passive immunization
•
•
•
•
•
The most effective type of antibody response is
called a broadly neutralizing antibody (bNAb)
response
bNAbs can potently inhibit a broad array of different
HIV isolates from multiple clades
Unfortunately, no vaccine can induce the production
of bNAbs (as yet)
bNAbs have been isolated from the B cells of some
HIV-positive individuals (not present at sufficient
levels to benefit the individual)
These isolated bNAbs are being manufactured and
can be administered via infusion or subcutaneous
injection (passive immunization)
Single 3BNC117 infusion – Antiviral activity
106
HIV RNA (copies ml-1)
HIV RNA (copies ml-1)
30 mg/kg
105
104
103
102
101
-7
0
7
14 21 28
Days after infusion
42
56
1
0
2D1
2C1
2D3
2E1
2E2
2E3
2E4
2E5
-1
-2
0
7
14
21
28
42
56
Days after infusion
Dr. Sarah Schlesinger, Rockefeller University, AVAC webinar: New Frontiers in HIV Prevention, Treatment and
Cure, Tuesday April 21, 2015: http://www.avac.org/blog/new-frontiers-hiv-prevention-treatment-and-cure
Passive immunization in cure research
•
•
•
Some antibodies have the capacity to flag
infected cells expressing HIV antigens for
destruction by antibody-mediated cellular
cytotoxicity (ADCC) and antibody-mediated
cellular phagocytosis (ADCP)
Destruction performed by natural killer (NK)
cells and monocytes
As with therapeutic vaccines, interest in
combining passive immunization with LRAs
(promising results in humanized mice)
Ariel Halper-Stromberg et al. Broadly Neutralizing Antibodies and Viral Inducers Decrease Rebound from HIV-1 Latent
Reservoirs in Humanized Mice, Cell , Volume 158, Issue 5, p989–999, 28 August 2014
Passive immunization in cure research
•
Ongoing studies of bNAbs in HIV-positive
individuals
• VRC01
• 3BNC117
•
Additional studies planned
• VRC01 + ART in acute HIV infection
• 3BNC117 effect on HIV reservoir, effect on viral load
rebound after ART interruption
• PGT121
• VRC07
• 3BNC117 + 10-1074
• bNAbs + LRAs
Antibody gene transfer
•
•
•
•
•
•
An alternative approach to bNAb delivery also being
studied
Employs adeno-associated virus (AAV) vector to
deliver gene for making bNAb(s) into muscle tissue
AAV persists and produces supply of bNAb
Method used with some success to deliver factor IX
to hemophiliacs
Ongoing Phase I trial of AAV encoding bNAb PG9 in
HIV- individuals in UK
AAV also being considered to deliver potent
antibody-like protein inhibitor of HIV (eCD4-Ig) based
on promising macaque results
Adoptive immunotherapy
Instead of infusing bNAbs, adoptive
immunotherapy infuses HIV-specific T cells
• T cells are extracted from an individual,
cultured with HIV antigens and expanded in the
laboratory, then reinfused into the individual
• Goal of promoting elimination of HIV-infected
cells (similar to therapeutic vaccination)
• Clinical trials ongoing
•
• HXTC (US CARE collaboratory)
• Autologous HIV-specific CD8 T cells (China)
Immune-based therapies (IBTs)
•
Broad category of therapies including:
• Substances produced by the immune
system (e.g. cytokines)
• Approaches that aim to work via
modulation of the immune system
Cytokines
•
•
Interleukin-7 (IL-7) studied as a latencyreversing agent but did not work (promoted
proliferation of latently infected cells)
IL-15 being studied as a potential latencyreversing agent & promoter of natural killer
cell activity
• Clinical trial of ALT-803 (recombinant human
super agonist interleukin-15 complex) due to
start soon
Cytokines
•
•
IL-21 has been reported to limit the viral
reservoir in SIV-infected macaques,
researchers plan to study in HIV-positive
individuals (already in trials for cancer)
Alpha interferon is approved for the
treatment of hepatitis C, several trials are
studying impact on the HIV reservoir
• Small study reported reductions in levels of
integrated HIV DNA
Toll-like receptor (TLR) agonists
•
•
Class of compounds that interact with
immune cell receptors involved in nonspecific recognition of pathogens (toll-like
receptors or TLRs)
Several TLR agonists being studied as
potential latency-reversing agents &
promoters of innate immunity
• MGN1703 (TLR-9 agonist)
• Poly-ICLC (TLR-3 agonist)
• GS-9620 (TLR-7 agonist)
James Whitney et al. Treatment With a TLR7 Agonist Induces Transient Viremia in SIV-Infected ART-Suppressed Monkeys, Abstract 108, CROI
2015, Seattle, Washington, February 23-26, 2015
Immune checkpoint blockers
•
•
•
•
Certain immune cell receptors known as
immune checkpoints (or negative regulators)
are involved in dampening immune
responses
Expression of these receptors can impair
HIV-specific T cell responses
Also appear involved in maintaining latently
infected CD4 T cells in quiescent state
Examples include PD-1, CTLA-4, LAG3, TIGIT
Immune checkpoint blockers
•
•
•
•
•
Antibodies that block these receptors (or the
ligands they interact with) may both
enhance HIV-specific T cell responses and
reverse HIV latency
Ongoing study of an antibody to PD-L1 in
HIV-positive individuals on ART
Plans to study an antibodies to PD-1, CTLA-4
Several of these antibodies are now licensed
treatments for cancers
Can have significant side effects, including
autoimmunity
Immune checkpoint blockers
Stephen Mason, Bristol-Myers Squibb, The potential role of PD-1/PD-L1 blockade in HIV Remission & Cure, Community Cure
Workshop, February 22, 2015 Seattle, WA
Ethical considerations for therapeutic
vaccines
•
Therapeutic vaccine trials often (although not
always) include ART interruptions to assess if
vaccine-induced immune responses can exert an
anti-HIV effect in the absence of ART
•
There is a possible risk that a therapeutic vaccine
could increase rather than decrease HIV replication
by creating additional CD4 T cell targets for the
virus
Ethical considerations for therapeutic
vaccines
•
Participation in a clinical trial of a therapeutic
vaccine candidate may preclude participation in
future trials of other therapeutic
vaccine candidates
•
The multiplicity of factors that can influence
adaptive immunity (genetics, sex, age) makes
diversity of trial participants particularly key
•
The words “therapeutic vaccines” may be
misleading and lead to therapeutic (or curative)
misconception
Future directions & challenges
•
Likely need for more combination studies
• May need cooperation of different corporate &
academic partners
• Raises complex regulatory (FDA) issues e.g. assessing
safety and activity of each component
Better understanding of effective immune
responses needed (correlates of immunity,
biomarkers of efficacy)
• Immunologic mechanisms can be complex and
unpredictable, relevance of animal models not
always clear
•
Future directions & challenges
•
•
•
Incentives for industry limited by lack of
precedents (no approved IBTs for HIV
although recent significant progress in
cancer)
History of immune-based approaches being
perceived as off-the-wall compared to
antiretroviral therapy
Research funding environment
Future directions & challenges
•
Defining success
• If a cure is not achieved (as defined by an
absence of any detectable HIV), what degree of
immune control of HIV might be considered
“remission”?
• Challenge of proving even strict immune control
of HIV is clinically equivalent to ART (e.g. elite
controllers may face elevated risk of
inflammation-related disease vs. individuals on
ART)
http://www.avac.org/cureiculum
Modules will contain:
Town Hall
Meetings
Concept
CROI 2014
PowerPoint
Teaching Sets
US AIDS Care
Conference,
October 4, 2014
Participatory
Activities &
Events
Visual/
Graphic
updates
(Phase 2
Launch)
NIH Martin Delaney
Collaboratories meeting
October 14, 2014
Pre- and
Post-Test
Assessments
Webinar
Recordings
CROI
February 2015
Launch
Upcoming Webinars
Dates (2015)
Topics
July 15
Informed Consent
August 6
Gene Therapy
August 27
Ethics of HIV Cure Research
September 10
Participation in HIV Cure Research
October 8
Animal Models
Module Contributors
Additional citations
Douek DC, Brenchley JM, Betts MR, et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature. 2002 May 2;417(6884):95-8.
Katlama C, Launay O, Gharakhanian S, et al. Evidence and potential immunotherapeutic applications of vaccine-induced antibodies against 3S, a highly
conserved motif of gp41, in HIV-1-infected patients treated with antiretroviral therapy (Abstract 145). Paper presented at: 30 Years of HIV Science
conference; 2013 May 21–23; Paris, France.
Andrieu JM, Chen S, Lai C, Guo W, Lu W. Mucosal SIV Vaccines Comprising Inactivated Virus Particles and Bacterial Adjuvants Induce CD8(+) T-Regulatory
Cells that Suppress SIV-Positive CD4(+) T-Cell Activation and Prevent SIV Infection in the Macaque Model. Front Immunol. 2014 Jun 30;5:297. doi:
10.3389/fimmu.2014.00297.
Caskey M, Klein F, Lorenzi JC, et al. Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015 Apr 8. doi:
10.1038/nature14411.
Gardner MR, Kattenhorn LM, Kondur HR, et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature. 2015 Mar
5;519(7541):87-91. doi: 10.1038/nature14264. Epub 2015 Feb 18.
Lam S, Sung J, Cruz C, et al. Broadly-specific cytotoxic T cells targeting multiple HIV antigens are expanded from HIV+ patients: implications for
immunotherapy. Mol Ther. 2015 Feb;23(2):387-95. doi: 10.1038/mt.2014.207. Epub 2014 Nov 4.
Sung JA, Lam S, Garrido C, et al. Expanded Cytotoxic T-cell Lymphocytes Target the Latent HIV Reservoir. J Infect Dis. 2015 Jan 13. pii: jiv022. [Epub ahead of
print]
Katlama C, Lambert S, Assoumou L, et al. Impact of interleukin-7 and raltegravir + maraviroc intensification on total HIV DNA reservoir: results from
ERAMUNE 01 (Abstract 170aLB). Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 2013 March 3–6; Atlanta, GA.
Jones RB, Mueller S, O’Connor R et al. Cytotoxic T-lymphocytes in combination with the IL-15 superagonist ALT-803 eliminate latently HIV-infected
autologous CD4+ T-cells from natural reservoirs (Abstract 2008). Keystone Symposia: Mechanisms of HIV Persistence: Implications for a Cure, 2015 April 26–
May 1, Boston, Massachusetts, USA
Micci L, Ryan E, McGary C, et al. IL-21 Reduces Inflammation and Virus Persistence in ART-Treated SIV-Infected Macaques (Abstract 168). 22nd Conference
on Retroviruses and Opportunistic Infections, Seattle, Washington 2015 Feb 23-26. Available from:
http://www.croiwebcasts.org/console/player/25831?mediaType=slideVideo&
Azzoni L, Foulkes AS, Papasavvas E, et al. Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cellassociated HIV DNA integration. J Infect Dis. 2013 Jan 15;207(2):213-22. doi: 10.1093/infdis/jis663. Epub 2012 Oct 26.
Winckelmann AA, Munk-Petersen LV, Rasmussen TA, et al. Administration of a Toll-like receptor 9 agonist decreases the proviral reservoir in virologically
suppressed HIV-infected patients. PLoS One. 2013 Apr 26;8(4):e62074. doi: 10.1371/journal.pone.0062074.
DaFonseca S, Chomont N, El Far M, Boulassel R, Routy J and Sékaly R. Purging the HIV-1 reservoir through the disruption of the PD-1 pathway. J Int AIDS Soc.
2010; 13(Suppl 3): O15. Published online 2010 Nov 4. doi: 10.1186/1758-2652-13-S3-O15
Autran B, Murphy RL, Costagliola D, et al. Greater viral rebound and reduced time to resume antiretroviral therapy after therapeutic immunization with the
ALVAC-HIV vaccine (vCP1452). AIDS. 2008 Jul 11;22(11):1313-22. doi: 10.1097/QAD.0b013e3282fdce94.