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A Vaccine for HIV:
31% There?
African American HIV University
May 19, 2014
Otto Yang, M.D.
Division of Infectious Diseases, Department of Medicine, UCLA
Department of Microbiology, Immunology, and Molecular Genetics, UCLA
AIDS Healthcare Foundation
Short Version of This Lecture:
No
Why We Still Need a Vaccine
Why We Still Need a Vaccine
A Vaccine: Still the Best
Long Term Solution
• Drug treatments: expense, infrastructure
for delivery and monitoring, treatment
fatigue, toxicities, resistance
• Behavior-based prevention: human
nature, cultural issues
• Vaccines: capacity for global impact (e.g.
smallpox, polio), limited requirements for
infrastructure and adherence
The News: RV144
RV144: Mission Accomplished?
• Placebo-controlled
study of 16,000
people
• Novel combination
of two vaccines for
cellular and
humoral immunity
• 31% protection
“A job well done”?
Objectivity?
PI of CHAVI ($300,000,000 consortium)
PI of the $105,000,000 study
….
But where are the real numbers???
ITT: 76/7325 (1.04%)
Vs
56/7347 (0.86%)
PP: 50/6002 (0.83%)
Vs
36/5874 (0.61%)
mITT: 74/7325 (1.01%)
Vs
51/7347 (0.69%)
This would have
“confused everybody”
Pre-Test Probability?
Pre-Test Probability?
Cellular Immune Component
Humoral Immune Component
RV144 was a test of a T-cell
vaccine that failed to make T
cell responses paired with an
antibody vaccine that failed to
make protective antibody
responses
So the vaccine somehow worked through a
new and unintended mechanism???
How Did We Get Here?
300 Years Earlier….
Virus Vaccine Technology:
Empiricism
• 1700s: Cowpox mimic of smallpox
(Jenner and others)
• 1950s: Killed virus (Salk) and live
attenuated virus (Sabin)
• 1970s: Subunit (Hilleman)
• Common theme: Recapitulate infection
• Protective mechanism: Who cares?
Virus Vaccine Technology:
Empiricism
• 1700s: Cowpox mimic of smallpox
(Jenner and others)
• 1950s: Killed virus (Salk) and live
attenuated virus (Sabin)
• 1970s: Subunit (Hilleman)
• Common theme: Recapitulate infection
• Protective mechanism: Who cares?
Successful Vaccines Mimic Naturally
Successful Immunity
Immune Response
Infection
MIMICKED
BY
VACCINE
(LAG)
First
Exposure
Subsequent
Exposure
Naturally Immunity Is Unsuccessful in
HIV-1 Infection
Acute Infection
(Flu-Like Illness)
Immune Response
Infection
Progression to
AIDS and Death
Asymptomatic Phase
(LAG)
Classical vaccine strategies that mimic natural
immunity
are therefore unlikely to
work, because
First
Infection
Subsequent
Exposure
Exposure
natural immunity fails in HIV-1 infection.
Back to the Basics….
Vaccines generate immune
“memory”
What memory responses work
against HIV?
• B Lymphocytes- Neutralizing Antibodies
• CD8+ Cytotoxic T Lymphocytes (CTLs)
• CD4+ Helper T Lymphocytes (HTLs)
Adaptive Immunity in a Nutshell
• Adaptive immune cells (B and T lymphocytes)
recognize non-self through specific receptors
(BCRs and TCRs)
• Receptors are generated through random
genetic recombinations (about 1015 different
TCRs are possible)
• Self-reactive receptors are weeded out
• Binding of the receptor causes a cell to mature
and divide
• Immune responses are generated by natural
selection (clonal expansion)
Adaptive Immunity in a Nutshell
Y
Y
Y
CTL
HTL
Y
VIRUS
Y
Y
Y
Y
B
Y
Y
Y
Y
Antibodies?
• The virus surface has the Env protein
that is used by the virus to bind cells to
infect them
• Antibodies can bind Env and interfere
with this process
Hope for Antibodies?
Antibodies Don’t Control HIV-1
in Infected Persons
Johnston and Fauci, NEJM 2007, 356:2073-2081
Difficulties Making
Neutralizing Antibodies
CD4 binding
pocket is
hidden in a
deep crevice
Envelope is heavily
coated with sugars
CCR-binding
region is
covered until
engagement
with CD4
Fusion domain
is covered until
CCR5
engagement
Envelope sequence is highly variable
Willey et al, Trends in Microbiology 2008, 16:596-604
Neutralizing Abs
NO NO NO
NO NO
NO
NO
NO
NO
NO
NO
NO
NO
YES
NO
NO
NO
NO
NO
NO
NO
YES
NO
NO
NO NO
YES
http://www.niaid.nih.gov/about/yearinreview/advances/scientificfindings/Pages/RecentSuccessesinDevelopinganHIVVaccine.aspx
+
CD8
Cellular Immunity:
Cytotoxic T Lymphocytes
CTL
Release of
Cytolytic Granules
and Cytokines;
Signals for Apoptosis
Infected Cell
Antigen-Driven
Proliferation
(Clonal Expansion)
CTL Recognition of Infected Cells
CTL
Infected Cell
HLA-I Epitope Motifs And Specificity
Pathogen protein sequence
Epitope
Epitope
Two different HLA-I molecules: Different epitopes
CTLs in HIV-1 Infection
• Temporal associations with changing
viremia
• HLA-I associations with disease progression
• GWAS studies mainly map to HLA-I
• Major factor in HIV-1 sequence evolution in
vivo
• SIV-macaque model: CD8+ T cell depletion
in vivo leads to sharply increased viremia
• In vitro studies of HIV-1-specific CTL: Potent
antiviral activity (cytolysis)
HIV-1-Specific CTLs Partially
Control Infection
Acute Infection
(Flu-Like Illness)
Immune Response
Infection
Asymptomatic Phase
Infection
Progression to
AIDS and Death
Setpoint Viremia Determines
Disease Progression
100
0
0
(Weeks)
(Years)
CTLs determine setpoint, setpoint determines disease
progression, thus the rationale for CTL-based vaccines to
prevent disease if not prevent infection
20
20
A “Good” CTL Vaccine :STEP Trial
Failure of CTLs?
The hope…
The reality
Vaccine: 24/741
Control: 21/762
VL 40k versus 37k
Once Is Was Not Enough
Vaccine: 27/1250
Placebo: 21/1244
VL similar
CTL-Based Vaccines That Mimic
Nature Won’t Work
• Cope with the genetic diversity of HIV-1
• Generate CTL responses at mucosal sites
• Access the HLA-I pathway to elicit CTL
responses against HIV-1 sequences
Mimicking HIV:
Giving CTLs the Same Choices
HIV
Vpu
Rev
Tat
Vif
Gag
Pol
Env
Nef
Vpr
Step Vaccine
Gag
Nef
Pol
HVTN505 Vaccine
Gag
Env
Pol
The High Mutation Rate of HIV-1 Is
a Huge Barrier to Immune Control
• Both antibodies and CTLs work by using
receptors to bind sequences in HIV
• Each day, about 10 billion viruses are
made in a person
• Each virus has an average of 1 random
mutation in its 9600 base RNA sequence
• EVERY possible single or double
mutation combination is made daily in
vivo
Overwhelming Problem of HIV-1 Diversity
From Korber, et al., British Medical Bulletin 2001: 58; 19-42.
Focus Immunity on Constrained Sequences,
Rather Than Delivering Entire Proteins?
OO Yang, PLoS One 2009, 4:e7388.
The Need for Speed
Haase, Nature 2010, 464:217
Speed of Remembering a Vaccine
O Yang, Unpublished
DNA
Gag/Env/Nef
rAd5
Gag/Env/Nef
Is There a Way to Vaccinate Constantly???
CTL and Chronic CMV
Piggyback Ride on CMV
Questions?