Transcript Document

HIV
Vaccine Research & Development
Prof. Omu Anzala
KAVI
Department of Medical Microbiology
School of Medicine
University of Nairobi
A DECADE OF VACCINES
What is a “Vaccine”
• The term vaccine derives
from Edward Jenner's 1796
use of the term cow pox
(Latin) variola vaccinæ,
adapted from the Latin
vaccīn-us, from vacca cow),
which, when administered
to humans, provided them
protection against smallpox
A Decade of Vaccines
Global Commitment to:
• Increase uptake of the current
childhood vaccines.
• Increase the use of underused
vaccines
• Accelerate research & development
of 6 new vaccines
( diarrhea & pneumonia, TB, Malaria
and HIV vaccines)
Is the discovery of an HIV vaccine
possible?
 Basic and Epidemiology research in HIV/AIDS has been
pointing to this fact.
 RV144 trial in Thailand demonstrated for the first time modest
protection against HIV infection.(Canary-pox-vector prime
plus protein-subunit boost)
 Discovery of potent and broadly neutralizing antibodies
RV 144
Study Vaccines
• ALVAC®-HIV (vCP1521)
• Recombinant canarypox vector vaccine genetically
engineered to express HIV-1 gp120 (subtype E: 92TH023)
linked to the transmembrane anchoring portion of gp41
(subtype B: LAI), and HIV-1 gag and protease (subtype B:
LAI).
• AIDSVAX® B/E
• Bivalent HIV gp120 envelope glycoprotein vaccine
containing a subtype E envelope from the HIV-1 strain
CM244 and a subtype B envelope from the HIV-1 strain
MN.
RV 144 The Analyses
• - the intention-to-treat and per-protocol
analyses,
• showed vaccine efficacies of 26.4% (P = 0.08)
• and 26.2% (P = 0.16), respectively.
• a possible, albeit modest,protection
The ADCC mechanism: bridging the gap between
innate and adaptive immunity
antibody
granules
antigen
Fc receptors (CD16, C
EFFECTOR CELL
TARGET CELL
New and exciting discovery
• Broadly neutralizing antibodies.
• Revealed vulnerable targets on the virus that
are now being exploited for
vaccine design.
Antibody Attack on Targets:
What we knew and what’s NEW
Viral Membrane
NEW
CD4bs
“b12”
gp41
“Trimer”
“PG9” and
“PG16” 4E10”
gp120
MPER
“2F5” and
V3
CD4
Wyatt and Sodroski Science 1998
Huang et al Science 2005
Phogat, Wyatt Curr Pharm Design 2007
Cell Membrane
CCR Glycan
5
shield
target “2G12”
HIV Life Cycle & Vaccine Design
Neutralizing Antibodies
Cell Mediated
Immunity
HIV Vaccine Clinical Research
IAVI 002
(2001)
IAVI 004
(2002)
IAVI 008
(Roll over)
IAVI 010
(2003)
V001
(2006)
Candidate
vaccine
DNA
MVA
DNA+MVA
DNA+MVA
Multi-clade
DNA/Ad5
Sample Size
18
18
10
70
57
Enrolled
15:3
(M:F)
16:2
(M:F)
10
58:12
(M:F)
36:21
(M:F)
Recruitment
rate
(no/month)
4.5
4.5
10
12
14
Retention
rate
94.4%
(17/18)
94.4%
(17/18)
100%
98.6%
(69/70)
98.2%
(56/57)
Vaccine Research
On going Vaccine trials at KAVI
13
Ongoing Phase 1 clinical trials
PaedVac
•
•
•
•
•
•
•
•
•
•
Funded by EDCTP
MVA + EPI vaccination vs EPI vaccination (alone)
Safety, immunogenicity & interference with EPI vaccines
Infants vaccinated at 20 weeks - single IM injection
Immunogenicity - ELISPOT & Cultured ELISPOT
Gambia trial over (48 infants) - data being analyzed
Nairobi trial (63/72 infants randomized)
Both sites, no vaccine related SAE
Immunogenicity data not yet out
Antibody titres to EPI being conducted
14
Ongoing Phase 1 clinical trials
Protocol B002
• Recombinant Fusion protein (F4co) in adjuvant (ASO1B or
ASO1E) + replication incompetent Ad35-GRIN
• F4co [p24-RT-Nef-p17 of HIV-1clade B Gag, Pol, Nef)]
• Ad35-GRIN [with HIV-1 clade A gag, RT, integrase, nef)
• Phase 1, double blind, randomized placebo controlled
• 140 participants (112 vaccine/28 placebo)
• Ages 18-40 yrs
• Low risk, healthy, HIV –ve, Ad35 antibodies -ve
• Multisite study – Kenya, Uganda, Zambia
15
Ongoing Phase 1 clinical trials
Protocol B003
 Different combinations of recombinant Ad26 vector &
recombinant Ad35 (HIV-1 sub-type A env gene)
 Heterologous or homologous
 212 to be enrolled
 Multi-centre – Boston (USA), Rwanda, S/Africa
 KAVI-Kangemi recruiting
 Screened 85
 Enrolled 34
16
What are the challenges
• The virus impairs the immune systems
• Viral diversity
• The correlates of immunity or protection not fully
Mechanism of Action
Vaccines:
Death
Exposure
Infection
Disease
Recovery
Balancing safety and efficacy in HIV vaccine design
The Questions ??
 Would an HIV vaccine be useful if it was less than 100%
effective?
 Would a vaccine still be needed if current prevention
programs and antiretroviral therapy (ART) are
significantly expanded while the vaccine is still being
developed?
 Would a vaccine result in cost-savings?
Vaccines can take decades to develop
INFECTIOUS AGENT
(Disease)
AGENT LINKED
TO DISEASE IN …
Measles
VACCINE LICENSED
IN U.S. IN …
YEARS
ELAPSED
1953
1963
10
Hepatitis B
1965
1981
16
Human papilloma virus
(cervical cancer)
Early ’80s
to mid-’90s
2006
Rotavirus
(diarrheal disease)
1973
2006
Varicella zoster
1953
1995
1906
1948
42
1908
1955
47
1889
1981
92
1884
1989
105
1893
—
116
1983
—
28
(chickenpox)
Pertussis
(whooping cough)
Polio
Haemophilus influenza
Typhoid
Malaria
Human immunodeficiency virus
(HIV/AIDS)
12-25
33
42