Download Vaccine Development

HIV vaccine research and development:
current status, challenges and opportunities
Thumbi Ndung’u, BVM, PhD
HIV Pathogenesis Programme
Doris Duke Medical Research Institute
Nelson R. Mandela School of Medicine
University of KwaZulu-Natal
Clinical trial evidence for preventing sexual
HIV transmission – July 2011
Study
Treatment for prevention
Effect size (CI)
96% (73; 99)
(Africa, Asia, America’s)
PrEP for discordant couples
73% (49; 85)
(Partners PrEP)
PrEP for heterosexuals
63% (21; 48)
(Botswana TDF2)
Medical male circumcision
54% (38; 66)
(Orange Farm, Rakai, Kisumu)
PrEP for MSMs
44% (15; 63)
(America’s, Thailand, South Africa)
STD treatment
42% (21; 58)
(Mwanza)
Microbicide
39% (6; 60)
(CAPRISA 004 tenofovir gel)
HIV Vaccine
31% (1; 51)
(Thai RV144)
0%
10
20
30
40
50
60
70
Efficacy
80
90 100%
Major Infectious Disease Cases in U.S. before
and after Vaccine Availability
Year
Cases in
1994
%
Change
Diptheria 206,939
1921
2
-99.9%
Measles
894,134
1941
963
-99.9%
Mumps
152,209
1968
1537
-99.9%
Pertusis
265,269
1934
4617
-99.9%
Polio
12,269
1952
0*
100%
Rubella
57,686
1969
227
-99.9%
Tetanus
1,560
1923
51
-99.9%
Disease
Total
Cases
Duration between discovery of microbiologic
cause of selected infectious diseases and
development of a vaccine
Disease
Years to develop vaccine
Typhoid
105
Haemophilus influenzae
92
Pertussis
89
Polio*
47
Measles
42
Hepatitis B
15
HIV
30…
*In the 1930s, two experimental polio vaccines failed because they were
determined to be unsafe, and polio vaccines were almost abandoned.
Source: Modified from H. Markel, NEJM, August 25, 2005
Vaccines in brief
• Effective disease prevention strategies
• Used for decades around the world, most
commonly in children
• Very safe when manufactured and used properly
• Very cost-effective compared to treatment
• Eliminated smallpox worldwide, almost polio…
Steps to an HIV Vaccine
Stage One:
Ideas
(Lab/Basic)
Vaccine
Ideas
Best Vaccine
Ideas
Experimental
Vaccines
Test in
tubes
and other
laboratory
equipment.
Stage Two:
Animals
(Pre-Clinical)
Stage Three:
People
(Clinical)
Stage
Four:
Stage Four:
Delivery
Delivery
(Licensure)
(Licensure)
Experimental
vaccines are
produced in
small amounts
and tested and
improved in
animals. The
vaccines that
seem safe and
most effective
in animals are
then considered
for testing in
people.
Vaccines are
tested in people
in a series of
studies. This
process takes
years.
Once an
an
Once
HIVvaccine
vaccineisis
HIV
found to
to be
be safe
safe
found
and
effective,
and effective, itit
must be
be delivered
delivered
must
around
the
world
around the world
topeople
peoplewho
who
to
need it.
it.
need
How do vaccines work?
Immune Responses
Humoral
Neutralizing
Antibodies
stop the virus
entering cells
Cellular
Cytotoxic T cells (CTL)
destroy cells infected with
HIV. Helper CD4 T cells
stimulate immunity
Aims of a Prophylactic HIV Vaccine
Induces sterilizing immunity HIV is never
detected in the body
(Ultimate goal, but may not be possible)
Induces immunity that allows transient
HIV replication
Induces immunity that holds the virus at low
levels such that both progression to AIDS
and transmission are prevented
Past HIV Vaccine Concepts
Although only three concepts have undergone clinical efficacy testing
to date, each HIV vaccine efficacy trial has yielded unexpected
outcomes that have transformed the HIV landscape.
2003
2005
2003: AIDSVAX
STUDIES
VaxGen Env gp120
Humoral Immunity
• Phase III studies in highrisk subjects in the
US/Thailand
• Elicited type-specific Abs
but not broadly reactive
NAbs
• No efficacy
2007
2009
2007: STEPPHAMBILI STUDIES
Merck Ad5Gag/Pol/Nef
Cellular Immunity
2009: RV144
Sanofi ALVAC prime,
Phase IIb study in high-risk
subjects in North/South
America and South Africa
•Elicited cellular immunity
by IFN-γ ELISPOT assays
•No efficacy, possible
increased HIV-1
acquisition
•Phase III study in low-risk
subjects in Thailand
AIDSVAX gp120 boost
Humoral and Cellular
Immunity
•31% reduction in HIV-1
acquisition with no viral
load effect
Advancing HIV vaccine candidates to efficacy trials will accelerate
progress in the field, bringing us closer to an effective global
vaccine.
from Nelson Michael and Jerome Kim
June 2010
Why haven’t these vaccines worked?Scientific Obstacles
• The natural immune response to HIV infection does
not control the virus
• The natural immune response to HIV infection does
not protect against superinfection
• Enormous sequence variability. We do not know how
to construct an immunogen to cover this sequence
variability
• We do not know what constitutes a protective
immune response
Relative Genetic Diversity: HIV-1 and
Influenza A
Annual global
Influenza A
HIV-infected
patient
One HIV-1
subtype
All HIV-1 subtypes,
sub-subtypes, CRF
Adapted from Francine McCutchan and from Korber B, et al. Brit Med Bull 2001;
58:19-42.
What are Mosaic Antigens?
Algorithm to Generate a k=4-Valent Mosaic Vaccine
Input: Single clade or M group
Iterations improve the populations,
improve the cocktail
Ad35, Ad26 and other vectors
Fischer et al. Nat. Med. 2007; 13:100-106
SIV challenge revealed an entirely new
pattern of protection in animals given
CMV vectors!
Group A (CMV/CMV)
n=6
p = .0017
Plasma Viral Load
109
108
Group B (CMV/Ad5)
p < .0001
109
108
n=5
109
Group C (DNA/Ad5)
108
n=9
107
106
106
106
106
105
105
105
105
104
104
104
104
103
103
102
102
n=6
102
n=7
103
102
0
28 56 84 112 140 168 196 224
0
28 56 84 112 140 168 196 224
n = 27
108
107
103
107
Group D (Controls)
109
107
0 28 56 84 112 140 168 196 224
n=1
0
28 56 84 112 140 168 196 224
Time Post Infection (days)
54% (13/24) of CMV vector-vaccinated RM, upon infection, manifested
immediate virologic control, bringing plasma virus to undetectable
levels, and 12 of these 13 maintained this stringent protection for >52
weeks. TEM biased, high immunogenecity, responses indefinitely
maintained, no Ab responses
Evolution of a T cell HIV/AIDS Vaccine Paradigm:
Old Paradigm:
2006
Vaccine-elicited immunity controls infection below
threshold for transmission
2010
New Paradigm:
Vaccine-elicited immunity
prevents or aborts infection, or
provides early complete control.
Stanley Plotkin, Review in CVI, 2010
"Correlates of protection induced by
vaccination"
• After the administration of nearly
all vaccines, prevention of
infection correlates with the
induction of specific antibodies
• It is likely that vaccines of the
future, such as those for HIV, will
obey the same paradigm
• Promising data on neutralizing
antibodies in humans and in
monkey models
New Minds: Making Breakthrough
Discoveries
Nobel Laureates 1901-2003 in Three Disciplines Stratified
by Age at Time of Award-Winning Discovery
Dietrich, Arne, and Narayanan Srinivasan. 2007. The optimum
age to start a revolution. Journal of Creative Behavior. 41: 54-74.
So, are we closer to developing a vaccine
against HIV?
Most certainly YES...
• First sign of protection in humans
• Significant advances in basic sciences
BUT……
• We probably need to expect more failures than
successes
• A vaccine is NOT around the corner
• It will NOT be a magic bullet
• We need to do more basic and clinical research
• This effort needs public and government support
Acknowledgements
• Dan Barouch- Harvard Medical School
• Loius Picker- Oregon
• Lynn Morris- NICD
• Many others whose ideas, data and slides I
have liberally borrowed