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AVAC
Global Advocacy for HIV Prevention
HIV Vaccines:
The basics
May 2016
Presentation Overview
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What is a vaccine?
How would an HIV vaccine work?
Where are we in the search?
What is needed now?
What is a vaccine?
• A substance that teaches the
immune system how to protect
itself against a virus or bacteria
• No effective HIV vaccine available
today
• HIV vaccines cannot cause HIV
• No vaccine is 100% effective
• Most vaccines licensed in the US
70%-95% effective
Why the interest in HIV vaccines?
• Proven prevention options have slowed HIV’s
spread – but thousands of people continue to get
infected daily
• There is a need for a range of HIV prevention
methods; there is no silver bullet
• Vaccines are one of the world’s most effective
public health tools
• Cost-effective – single or several doses likely
provide protection for years
How vaccines are crucial to ending HIV
Types of HIV vaccines
• Preventive vaccines
– Designed for people who are not infected with
HIV
– If effective, would reduce risk of infection
– May also reduce viral load set point after
infection
• Therapeutic vaccines
– Designed for people who are living with HIV
– If effective, would use the body’s immune system
to help control or clear HIV in the body
How do preventive vaccines work?
By teaching the body to recognize and fight a
pathogen
• Vaccine carries something that ‘looks and feels’
like the pathogen, but is not really the pathogen
• Body reacts by creating antibodies or killer cells and
a memory response
• Upon exposure to the ‘real’ pathogen, antibodies
and killer cells are waiting to respond and attack
Note: This is a general definition, not specific to HIV vaccines
How might preventive HIV vaccine work?
A preventive vaccine would teach the body to recognize
and fight HIV, should it be exposed
• Vaccine would carry a component that ‘looks and feels’ like
HIV, but is not HIV and cannot cause HIV infection
• Component might be a synthetic fragment of HIV known to
generate an immune response
• Body would react by creating antibodies and/or killer cells
and a memory response
• Upon possible exposure to HIV, antibodies and killer cells
would be waiting to prevent and/or control infection
Immune responses
Preventive HIV vaccines are meant to elicit two arms of
the immune system – humoral and cellular
(1) Humoral immunity
• Primary action of humoral
arm is creating antibodies
• Antibodies are Y-shaped
proteins developed in
response to a pathogen to
prevent infection
Immune responses
Preventive HIV vaccines are meant to elicit two
arms of the immune system – humoral and cellular
(2) Cellular immunity
• Cytotoxic T
lymphocytes and Thelper cells
• Cells recognize HIVinfected cells and kill
them
Preventing vs. controlling infection
HIV
PREVENT
ESTABLISHED
INFECTION?
*****
C
A
Vaccine
Administered
B
HAART
A. Lower Initial Peak of Viremia
B. Lower Set Point
Courtesy of HIV Vaccine Trials Network
C. Delay Progression
How have many vaccines been made?
• Live attenuated
vaccines (examples:
measles, mumps, and
rubella)
• Whole killed virus
vaccines (example:
influenza and rabies)
How are HIV vaccines made?
Recombinant vaccines
• DNA vaccines
• Vector vaccines
• Subunit vaccines
Do not contain HIV – only synthetic copies of
fragments of HIV that will create an immune response
but do not cause HIV infection
Developing an HIV vaccine is difficult
• Numerous modes of transmission
• HIV kills the very immune cells used in defending
the body against HIV
• HIV makes many copies of itself and mutates,
making itself unrecognizable to the immune system
• Mutation leads to different subtypes of the virus
throughout the world
Vaccine research in history
Duration between discovery of microbiologic cause of selected infectious diseases and development of a vaccine
Virus or bacteria
Year cause
discovered
Year vaccine
licensed
Years elapsed
Typhoid
1884
1989
105
Haemophilus Influenzae
1889
1981
92
Malaria
1893
None
–
Pertussis
1906
1995
89
Polio
1908
1955
47
Measles
1953
1995
42
Hepatitis B
1965
1981
16
Rotavirus
1973
1998
25
HPV
1974
2007
33
HIV
1983
None
–
Source: AIDS Vaccine Handbook, AVAC, 2005
HIV vaccine efficacy trial results
YEAR
PRODUCT/ CLADE/
TRIAL NAME
LOCATION
#
RESULT
2003
AIDSVAX B/B
VAX003
Canada,
Netherlands, Puerto
Rico, US
5,417 No effect
2003
AIDSVAX B/E
VAX004
Thailand
2,546 No effect
2007
MRK-Ad5 B
Step
Australia, Brazil,
Canada, Dominican
Republic, Haiti,
Jamaica, Peru,
Puerto Rico, US
3,000 Immunizations halted early for futility;
subsequent data analysis found potential for
increased risk of HIV infection among Ad5seropositive, uncircumcised men.
2007
MRK-Ad5 B
Phambili
South Africa
2009
ALVAC-HIV (vCP1521)
and AIDSVAX B/E
Thai Prime-Boost/RV
144
Thailand
2013
DNA and Ad5 A/B/C
HVTN 505
US
801 Immunizations halted based on Step result.
16,402 Modest effect (31.2%)
2,500 Immunizations halted early for futility; vaccine
regimen did not prevent HIV infection nor reduce
viral load among
vaccine recipients who became
www.avac.org/presentations
infected with HIV; follow-up continues.
Pox-Protein strategies
• In 2009 clinical study in Thailand (‘RV144’) showed evidence that a
vaccine can reduce HIV risk
– Pox-protein, prime-boost regimen using canary pox (ALVAC) and
manufactured HIV protein-GP120
– Moderately effective – 31% protection; not licensable
– Follow up research identified possible explanations for vaccinerelated protection and avenues for improvement
• New clinical trials launched by P5 in southern Africa in January 2015
– Modified regimen being tested in South Africa; potential efficacy
trial that might lead to licensure could start in late 2016
– Other regimens being tested for proof-of-concept, improved
responses
More information about Rv144 and the follow-up at: http://hivresearch.org/research.php?ServiceID=13
Antibody research
• 100s of broadly neutralizing antibodies (bNAbs) identified since 2009
– Work against majority of HIV strains
– Target limited number of sites on HIV surface
• Direct transfer of antibodies—passive immunization—being tested as
prevention, treatment, part of cure
– Multiple bNAbs tested in early clinical trials: www.bnaber.org
– Many show safety, tolerability, significant viral reduction among HIVpositive participants
– First large-scale study of bNAb VRC01 initiated April 2016 for proof of
concept, called AMP study: www.ampstudy.org
– Hope to increase potency of bNAbs, duration of responses
– Possible alternate delivery mechanisms to infusion, e.g. series of
subcutaneous shots
– Possible future combination bNAb approaches
Antibody research
Future priorities
• P5 – large-scale trials following RV144 results in South
Africa, possibly Thailand
• Janssen-sponsored product and clinical testing of ‘mosaic’
(cross-clade) based strategy
• Implications of AMP Study results for future of bNAb
research and vaccine design
• Advancement of candidates/strategies in smaller-scale trial
• Pre-clinical discovery and advancement of individual bNAbs
and combinations in clinical trials
• Continued identification of novel vectors, adjuvants and
other strategies for improved candidates
Advocates’ checklist
• Monitor timelines of clinical trials, especially delays
and the reasons for them
• Ensure diversity of approaches beyond pox-protein
strategy, exploring novel directions for vaccine
design
• Push for more stakeholder involvement, e.g., on
trial design, standard of prevention/care, decisionmaking on moving candidates through the clinical
pipeline
Key resources
• AVAC: www.avac.org/vaccines
• Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID)
o At Duke: www.chavi-id-duke.org
o At Scripps: www.cavi-id.org
• Collaboration for AIDS Vaccine Discovery: www.cavd.org
• Global HIV Vaccine Enterprise: www.vaccineenterprise.org
• HIV Px R&D Database (PxRD): www.data.avac.org
• HIV Vaccines & Microbicides Resource Tracking Working Group: www.hivresourcetracking.org
• HIV Vaccine Trials Network (HVTN): www.hvtn.org
• International AIDS Vaccine Initiative (IAVI): www.iavi.org
• Military HIV Research Program (MHRP): www.hivresearch.org
• NIAID: www.niaid.nih.gov/topics/hivaids/research/vaccines/Pages/default.aspx
• NIH Vaccine Research Center (VRC): www.vrc.nih.gov
• Pox-Protein Public-Private Partnership (P5): www.hivresearch.org/media/pnc/9/media.749.pdf
Connect With Us
• Questions, comments and requests for materials should be
sent to [email protected]
• For the latest news and updates, sign up for our Advocates’
Network mailing list at www.avac.org/signup or follow us on
Facebook at www.facebook.com/hivpxresearch and on
Twitter at www.twitter.com/hivpxresearch
The Basics of
HIV Cure Research
HIV Cure Research Training Curriculum
HIV and Cure Basics Module Presented by Jessica Salzwedel:
July 2016
The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure research science accessible to the
community and the HIV research field.
Objectives
Describe:
●Different ways to conceptualize an HIV
cure
●Why it is difficult to cure HIV
●Rationale for exploring a cure
●Current cure strategies being researched
What is an
HIV Cure?
What Does
HIV Cure Mean?
What Does HIV Cure Mean?
●No need for on-going medication (ARV
treatment)
●No symptoms
●No viral progression/immune damage
●No risk of transmission
The Language of “Cure”
● Sterilizing/Eradication● HIV is completely removed from every cell in
the body
● Person is HIV-free (virus free)
● Functional/Remission● HIV is NOT completely gone from the body
● All requirements from previous slide met
● HIV has potential to resurface.
What is an
HIV Cure?
Why is it so
Hard to Cure HIV?
Why is HIV so Hard to Cure?
●HIV enters a cell and integrates into the
cell’s DNA
●Most cells recognize infection- causing
cell death
●A few infected cells become “long-lived”
memory cells or “resting memory” cells
●The collection of long-lived memory cells
is called the Latent Reservoir
Why is HIV so Hard to Cure?
Why is it so Hard to Cure HIV:
Establishing the Latent Reservoir
HIV
Latent Reservoir
Naïve CD4+ T cell
Cell
Death
Activated
CD4+ T cell
Cell
Survival
Resting
Memory
CD4+ T cell
Adapted from D. Persaud
Why is it so Hard to Cure HIV:
Establishing the Latent Reservoir
Latent Reservoir
Reactivated
CD4+ T cell
Adapted from D. Persaud
Where is the HIV Reservoir?
● Brain
● Lymph nodes
● Peripheral blood
● Gut
● Bone marrow
● Genital tract
Adapted from A. Fauci
How Can the Reservoir be Measured?
●Reservoir size varies from person to person.
Different factors, like genetics, when ART
was initiated, and viral load during exposurewill influence reservoir size
●Obtaining samples from some tissues (e.g.
spleen, brain) can be difficult because of
location
●Currently, there is no standard test that
accurately measures the reservoir
How Can the Reservoir be Measured?
HIV DNA
Intact
VOA
Scale=100/106
Ho et al, Cell, 2013
Why is an HIV Cure Important?
●Disparity of access to care/HIV
treatment globally
●Medication burden
●Medication side effects
●Expense
HIV Cure: Proof of Concept
● HIV+ Acute Myeloid Leukemia
Patient
● Identification of HLA-identical,
CCR5Δ32 homozygous bone
marrow donor
● Chemo- and Radiotherapy
Conditioning
● Allogeneic stem cell transplant
● 7 years later: remains cured
What are the Research Stages?
Basic
science
Translational
research
Clinical (human)
trials
Basic
research
Preclinical
research
Concept
studies
Phase I
Smaller safety studies
Phase II
Larger, longer look at safety and immunogenicity
Phase IIb
Lab
studies
Even larger look at safety and efficacy
Animal
studies
Even larger look at safety and efficacy
Posteffectiveness
Post licensure activities
vary with each
product/intervention
Demonstration Project
Phase IV
Marketing studies
Product introduction
Phase III
Open-label extension (OLE)/Post-trial access
Safety and efficacy
Real-world
effectiveness
Population scale-up
Often a product
/intervention does not
progress in a linear fashion
License
What is an
HIV Cure?
Current Strategies
What is an
HIV Cure?
Kick and Kill
or
Shock and Kill
Kick and Kill
The Economist, July 17, 2011
What is Kick and Kill
●A two step approach that:
● Stimulates virus production from latent
cells
● Kills virus particles outside the cell and
infected cells
What is kick and kill?
LRA
Cell death
Latency Reversing Agents
●A category of drugs that
stimulate HIV-positive
long-lived memory cells
to begin producing virus
●HDAC InhibitorsHistone Deacetylase
Inhibitors have been
one of the class of
drugs being pursued in
the field
Notable LRAs
• TLR7- Agonist
• Bromodomain
Inhibitors
• Ingenol
What is an HDAC Inhibitor?
Current Challenges of Kick and Kill
●Measurement of reservoir size/Getting it
all
●New reservoirs
●Medication side effects
What is an
HIV Cure?
Immune Modulation
What are Immune Modulators?
●Category of research that
harnesses the innate and
adaptive immune system
to better recognize
and/or fight HIV
●All immune modulators
would likely need to be
used in combination with
each other or other
approaches
Innate immunity- No
specific response; first
line of defense like skin
Adaptive immunityTargeted responses to
specific pathogenscreating a whole army
dedicated to attacking
one enemy
How the Immune System Works
HVTN “Soldiers” of the Immune System
Therapeutic Vaccines
●Rationale: Strengthen or create new
and more effective immune responses
to HIV in people living with HIV
●Generate long-lived adaptive immune
responses to HIV that can continue to
control the virus without medication
Broadly Neutralizing Antibodies
●Broadly Neutralizing Antibodies (bNAbs)
are able to make many different mutations
of HIV harmless by binding to 1 of 3
places on HIV
●bNAbs are currently being explored for
use in HIV prevention, treatment and cure
Current Challenges of Immune
Modulation
●Complex regulatory issues because each
vaccine component will need to be
evaluated separately and in combination
●Animal models do not always translate to
humans
●Proving that strict immune control of HIV is
clinically equivalent or better than ART
What is an
HIV Cure?
Gene Alteration/Modification
What is Gene
Alteration/Modification?
●A process to edit the DNA inside immune
cells in some way to make the cell less
susceptible to HIV
●A process to edit the DNA inside immune
cells to increase the killing potential of
the cells
●A process to edit the DNA inside the
virus to reduce it’s ability to impact people
What is Gene
Alteration/Modification
Creating HIV Immunity
● HIV needs a receptor, CCR5,
to be present on a cell surface
in order to enter the cell and
cause damage
● One focus of gene therapy in
Other Tools Used
• CRISPR/Cas9
trials is to remove or block this
•
receptor
● Zinc Fingers, molecular
scissors used to edit genes,
are one of the main tools
being explored in clinical
research
Mega Tals
• TAL Effector
Nucleases
Creating HIV Immunity
Virus-Mediated Transfer of
Mobilization
Therapeutic Gene
Leukapheresis
OR
Bone Marrow Harvest
Isolation of Stem Cells or T
cells
Reinfusion
Patient
Challenges to Gene
Alteration/Modification
●Assuring only on-target modifications
made
●Unknown how much modification is
needed to produce benefit (therapeutic
threshold)
●Development of potential immunity to the
tools used to make gene alterations occur
●Current cost and scalability
What is an
HIV Cure?
Ethical Challenges
What Are the Social & Ethical
Challenges
●Balancing resources
●Risk versus reward
●Participant selection
●Trial design
●Cost
●Scalability
What Does an HIV Cure Need to Be?
●Safe
●Effective
●Durable
●Affordable
●Accessible
Questions
For additional information
visit: www.avac.org/CUREiculum
Acknowledgements