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Transcript
HKU Discovers a Novel AIDS DNA Vaccine
Dr Chen Zhiwei
Director and Principal Investigator
Dr Allen Cheung Ka-loon
Post-doctoral Fellow
Ms Zhou Jingying
PhD Candidate
AIDS Institute
The University of Hong Kong Li Ka Shing Faculty of Medicine
Updated Pandemic of HIV/AIDS by 2011
•An estimated 5 million people in Asia were living with HIV up till now.
(Source: UNAIDS 2013)
HIV/AIDS epidemic in Hong Kong
•
•
•
97.7% of HIV / AIDS cases were due to sexual transmission
4% prevalent rate was found among MSM (Men who have sex with men) in 2012.
With the increasing number of HIV / AIDS cases, an effective vaccine is necessary for
AIDS prevention and immunotherapy.
(Source: Virtual AIDS Office of Hong Kong 2013)
Current challenges against HIV/AIDS
• Lack of a Therapeutic Cure:
•
•
ssRNA,
Reverse transcriptase
CCR5
CD4
RNA-DNA hybrid
HAART (Highly active antiretroviral therapy, or
called cocktail therapy) suppresses patients’ HIV
load, extends patients’ life and reduces secondary
HIV spread.
Yet, issues of drug toxicity, drug resistance and
failure of eliminating HIV remain unsolved.
Integrase
dsDNA
Provirus
LTR
mRNA
ssRNA
Protease
Precursors
• Lack of an Effective Vaccine:
•
Current vaccines are rather weak and poorly
immunogenic.
Proteins
Illustration of HIV life cycle
and drug target
Role of CD8+ T cells in controlling HIV infection
• CD8+ T cells belong to a group of white blood cells known as
cytotoxic lymphocytes or killer T cells.
• They play a central role in cell-mediated immunity by killing
HIV-infected cells and cancer cells.
• The are well-known for their critical role of suppressing HIV
replication and eliminating latent reservoir in the body.
Unknown to Scientists
How to induce a high frequency of protective
HIV-specific CD8+ T cells for both preventive
vaccine and therapeutic cure?
HKU’s Discovery
1) We have discovered a novel AIDS DNA
vaccine that induces a high frequency of
broadly reactive, poly-functional and
protective CD8+ T cells against HIV.
2) This new vaccine works by targeting HIV
antigen to dendritic cells via the
PD1/PDL binding, which results in the
distinct and robust CD8+ T cell immunity.
Structure of HIV
Novel AIDS DNA Vaccine Design
- PD1-guided delivery of p24 to dendritic cell
Counts
Dendritic Cell
More effective to
induce robust CD8+
T cells.
p24fc
sPD1-p24fc
sΔPD1-p24fc
PD-L1
p24
PD-L2
Anti-rabbit Fc
Experimental Schedule
Antibody &
T-cell responses
Immunization
0 (weeks)
3
6
8
Memory
Response
30
TERESA-Gene Delivery Device
for in vivo electroporation (EP)
EP efficiently delivers DNA Vaccine
Novel AIDS DNA Vaccine Greatly Intensified
CD8+ T cells in a Dose-Dependent Way
ELIspot Assay
IFN-γ+/CD + Elispots
/
Splenocytes
2000
***
1600
1200
**
600
400
8
6
10
sPD1 sIgV-PD1
-p24-fc -p24-fc
20μg
sPD1 sIgV-PD1
-p24-fc -p24-fc
PBS
100μg
-Kd- AMQMLKDTI
tetramer
Tetramer Assay
sPD1-p24-fc
21.2
sIgV-PD1-p24-fc
0.6
PBS
0.2
H
2
CD8
Long Term Memory CD8+ T cells Response
30 weeks post-vaccination
p24fc
2.36%
sPD1-p24fc
29.3%
sΔPD1-p24fc
1.42%
PBS
1.85%
Positive control
31.8%
The novel AIDS DNA Vaccine induces long lasting anti-HIV memory CD8+ T
cells as compared with control vaccines.
Significant Protection against Lethal Viral
Challenges in Mice
100
90
***
80
70
60
p24fc
sPD1-p24fc
sIgV-PD-1-p24fc
PBS
0 1 2 3 4 5 6 7 8
Days after challenge
• (Left) The line with circle
illustrates that the new vaccine
significantly increases the body
weight of mice as compared with
control vaccines
WR-gagpol Titer (x103 PFU)/ml
Body weight (%)
Virulent vaccinia WR-gag Challenge
10
8
**
6
4
2
sPD1 sIgV-PD1
-p24-fc -p24-fc
PBS
• (Right) The number of lethal
virus has remarkably decreased
after vaccination.
IL-12 on CD11c+ DCs (%)
IFN-γ+/CD + Elispots/
splenocytes
Direct Comparison of Two Methods of
Antigen-Targeting to DCs
2000
*
1500
1000
500
8
6
10
p24fc
sPD1 α-DEC205 p41
-p24fc -p41
PBS
*
*
3.0
2.0
1.0
p24fc
sPD1 α-DEC205 PBS
-p24fc -p41
Early DNA vaccine (α-DEC205-p41)
•a vaccine published in JCI 2008 by Prof R. Steinman (2011 Nobel Prize in Medicine).
•DC-targeting: through DEC205
New AIDS DNA vaccine (sPD1-p24fc)
•New discovery by HKU
•DC-targeting: through PD1/PD-L interaction to induce a high frequency of CD8+ T cells
(left) and IL-12 releasing DCs (right).
•New vaccine is more effective in inducing higher frequency of CD8+ T cells
Mechanism of Novel AIDS DNA vaccine
Dendritic Cells
sPD1-p24
DC-targeting
α-DEC205-p24
cross-presentation
PD-L1/L2
DEC205
Rab14
MHC I
Rab5
CD40
Th1 cytokines
p24
Rab7
IL-12
CD8
Non-DC-targeting
IFN-γ
Rab9 Lamp1
 New discovery by HKU
Early finding by Prof
Steinman’s team
Traditional vaccines
Cytokines
Cytotoxicity
Cytokines
Cytotoxicity
MHC II
CD40
CD4
B
Antibodies
(IgG1/IgG2a)
Importance of the findings
•
Our findings shed light on how to induce a high frequency of
protective HIV-specific CD8+ T cells - important for an
effective vaccine to either prevent or cure AIDS.
•
The study obtained the international patent, implying that
Hong Kong researchers have capability to invent novel AIDS
vaccine
•
Our results provide new insights on how immune system
works in regulating CD8+ T cell responses.
•
Besides against HIV/AIDS, our new technique can be used
for making vaccines for prevention and immunotherapy
against other diseases (e.g. TB, Malaria and Cancer).
Questions and Answers
AIDS vaccine is
the ultimate
solution