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8/7/2019 Novel Vaccine Approaches (Yiming Shao)
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The Novel HIV Vaccine Approaches
---- A personal Prospective
Yiming Shao
National Center for AIDS &STD Prevention and Control
China CDC
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Over simplified design (1st 10 years) does not work
gp120 vaccine simply mimic HBV vaccine, using just peptide not even bother tomake it as a particle like the HBsAg is.
Shift from B cell to T cell vaccine (2nd 10 years) is not rightThe mainstream research stop nAb vaccine too early and shift to the CMI vaccinetoo fast, did not keep a proper balance of B/T cell immunity.
Major investments focus on few approaches is wrong
First gp120/V3 peptides, then Ad5 and MVA vectors.
100% safety ideology lead to 0% efficacy reality
Ignoring risk/benefit balance nature of vaccine and give up many moreimmunogenic vaccine approaches such replicating vector etc.
Pay not enough attention to the unique nature of HIV infection
Human immune system did not provide enough protection to HIV in naturalinfection. Business as usual approach is not work for AIDS vaccine
Lessons learned
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vector
vaccine
87
othors
19
Statistics of the 190 HIV vaccine clinical trials
Gp120 vaccine
50
DNA vaccine
23
Peptides
veccine
11
non-replication
(84)
NYVAC
3
Ad
23
MVA
20
ALVAC
31
Others
(7
Replicating
(3)
Insanity: doing the same thing over and over again and expecting
different results.
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Major scientific challenge to AIDS vaccine
Examples in nature: HBV HIVInfection after sera conversion minority allDisease after infection minority majorityMortality after disease minority almost all
Observation:
� HIV doesn¶t induce good protective immunity in natural infection� Most vaccines had been made are against pathogen who inducegood protective immunity in natural infection.
Conclusion:In evolution, human immune system is not strong enough
to control HIV infectionThe Key to a successful HIV Vaccine
To design a novel vaccine, which can re-engineer the humanimmune system overcoming the inherited weakness andacquiring the ability to block or control HIV infection .
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HIV-2/HIV-1 Envelope Glycoprotein Chimeras to DetectEpitope-specific Nabs
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CD4/b12-binding Site as HIV Vaccine Target
b12 footprint on gp120 surface CD4 footprint on gp120 surface Superposition of the two footprints
Complex Contact Area on gp120 (Å2) Contact Area on Outer Domain
CD4:gp120 880 67%
b12:gp120 787 82%
T. Zhou, L Xu, B. Dey, et al. Nature, 2007, 445:732-6
The CD4 binding surface on gp120 is
� functionally conserved, structurally stable and spatially accessible
� one of the major vulnerabilities of HIV
� can serve as a very attractive target for AIDS vaccine
F-15/E-3
F-17
F-19/20/21
LD
F-24
F-23
42%
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SCIENTIFIC BASIS OF THE PROTECTIVE ROLE OF
ALLO-IMMUNITY IN HIV OR SIV INFECTION
I Epidemiological Evidence in Humans
1. Sex workers with rare HLA may be protected.
2. Vertical transmission is less frequent in discordant mother-infant HLA.
3. Sera from multiparous women may neutralize HIV in vitro.
II Experimental Evidence in Humans
4. Systemic allo-immunization or mucosal allo-immunity elicited by sexual intercoursein
women induces resistance of CD4+ T cells to HIV infection in vitro.
III Experimental Evidence in Non-Human Primates
5. SIV grown in human T cells prevented human cell-grown SIV infection in macaques.
6. Human T cells or HLA-I or -II induced sterilizing immunity against SIV in macaques.
7. Vaginal or rectal mucosal alloimmunization of macaques induced resistance of CD4+
T cells to SIV infection.
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HIV Virion
HLA II HIV gp120 HSP70
TCR CD4 CCR5 CD40
T and Bcells, NK cells, DC, Macrophages
Rationale of the allogeneic-HIV-1-HSP70 Vaccine
HLA-I
CD8KIR
* * **
*Arthur et al 1992 (more HLA than HIVgp120)
**Gurer et al 2002 (similar amount of HSP70 as viral pol protein)
DextranBackbone
CD8 + T cells
TCRBiotinAvidin
F2 M
E chainPeptide
- -+
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Relationship Between Poxvirus ReplicationCompetence and Safety and Immunogenicity
Immunogenicity
Live, non-replicationcompetent poxvirus-
based vaccine
Live, poxvirus-based vaccine
with self-limiting replicationcapacity
Live, replication
competent poxvirus-based vaccine
Infection with immune-controlled replication
Safety
Infection with virusreplication and spread
Infection withoutreplication
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The two technologies for Small Pox vaccines in history
Animal derived vaccines Tissue culture derived vaccines
in US and Europe (New York in China (Tiantan strain)
and Copenhagen strains etc.)
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Phase I/II Clinical trials of recombinant VTT vaccines
for HAV , HBV, EBV, and Measles in children
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Phase I Clinical Trial Design of DAN Prime
Replicative Tiantan (rTV) Boost Strategy
Phase Subjects Vaccine Test PeriodIa 12 rTV 24W
Ib 36 3DNA+rTV 36W
Phase I trail application to SFDA in 2005
Approved for Phase Ia in 2007, Phase Ib in 2008
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Protection against pathogenic SIV in
rhesus macaques
Vaccine StrategyMonkeys Protection ( >3
log suppression of viralload)
Live attenuated 74/78 (95%)
All other strategies 18/256 (7%)
Koff, W. etal, Nature Immunology 2005
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The Development of Live Attenuated EIAV Vaccine
EIAV WTEIAV WT(Field Isolate)(Field Isolate)
LN40 LN40 (Pathogenic Strain)(Pathogenic Strain)
D510 (Highly Pathogenic)D510 (Highly Pathogenic)
DLV (Attenuated Vaccine)DLV (Attenuated Vaccine)
DDV (Attenuated Vaccine)DDV (Attenuated Vaccine)
16 Passages in Horse16 Passages in Horse
117Passages in Donkey117Passages in Donkey
123Passages in123Passages inDonkey LeukocyteDonkey Leukocyte
12Passages in Fetal12Passages in FetalDonkey Dermal CellDonkey Dermal Cell
8 lentiviruses,
2 Vaccines:
EIAV 1975, China
FIV 2002, USA
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LTR LTRgag
pol
env
S2
tat1 tat2
EIAVEIAV
6060
7878
6969 y
106106 y
9191 yy
2929 y yyy yyyy y
y yy
4040 y y y
t t l
11
2020
4040
6060
8080
100100
120120
100%100%
67%67%
58%58%
50%50%
8%8%
5252
0 1 2 3 4 5 6 7 8 9 kb
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Comparison of humoral immune responses induced by the attenuated
vaccine, the cloned attenuated vaccine and DNA/rVaccinia vaccines
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Novel vaccine approaches
Paper 1. Aaron Diamond AIDS R esearch Center
In Vivo Electroporation Enhances the Immunogenicity
of ADVAX, a DNA-based HIV-1 Vaccine Candidate
� In comparison to DNA vaccination alone, DNA vaccine delivered
through in vivo electroporation induced significantly improved
immune responses with stronger magnitude and wider bredth in
human subjects as demonstrated in the phase I trial
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Novel vaccine approaches
Paper 2. University of PennsylvaniaAnalysis of DNA compared to Ad5 vaccination, as single
and mixed modalities, demonstrates robust induction of
cellular immune responses in macaques
� They have previously reported dramatic increases in immune responses
induced by DNA vaccines delivered by electroporation (EP), resulting in
improved control of viral replication following a SIVmac251 challenge.
� This time they will show us some new data that subsequent Ad5
immunizations failed to boost responses while the DNA+EP group
generated T cell responses with a very very high magnitude. The T cell
response was higher in the DNA+EP group compared to the Ad5 group .
� This results is very encouraging. We have few reports so far that DNA
vaccination can induce immune responses comparable to those induced
by viral vectored vaccine candidates.
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Novel vaccine approaches
Paper 3. FIT Biotech, University of Tartu, CEA / Divisionof Immuno-Virology
Efficacy study of a T-cell-based DNA vaccine delivered
by intradermal electroporation (EP) in macaques
� Before challenge, all animals were immunized with DNA vaccine through ID
only, ID+EP or ID+EP+genetic-adjuvant apporaches, respectively.
� All animals were intrarectally challenged with pathossgenic SIVmac251.
� Plasma viral load was significantly reduced in the ID+EP group,but not other
two groups. Differences in anti-Gag responses may explain this observation.
� Reduction of SIV-DNA copies in rectal biopsies was observed in all thevaccinated animals.
These above 3 approaches may overcome the weakness of DNA vaccine
in delivery to human cells, a similar problem in gene therapy
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Novel vaccine approaches
Paper 4. University of Miami Miller School of Medicine Gp96-Ig-SIV vaccines
induce predominant immune responses at mucosal sites
� After the third immunization with cell secreted gp96-Ig-SIV vaccine, the
SIV-specific CD8 response was boosted to very high levels in the rectum
and jejunum.
� The cell secreted gp96-Ig-SIV vaccine is safe and can induce strong poly-
specific, multifunctional and predominant CD8 responses in mucosal
compartments.
� T cell responses in the mucosal sites are thought to be critical for protection
from SIV/HIV infection.
This is a novel design of the HIV vaccine, with adjuvant targeting
to DC, the most important antigen presenting cell of our body.
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Novel vaccine approaches
Paper 5. K arolinska Institutet
Impact of in vivo CD4 binding during HIV-1 Env trimer
immunizations of rhesus macaques
� Rhesus macaques were immunized with wt trimers or CD4 binding
defective trimers.
� Antibodies against the co-receptor binding site were elicited in animalsimmunized with wt trimers, but not in animals immunized with the CD4-
binding defective mutants. Differences in the quality of the in vitro
neutralizing antibody response were observed.
� Elimination of the Env-CD4 in vivo interaction region did not affect
vaccine-induced Env-specific T cell responses or levels of total elicitedbinding antibodies.
� A comparable decrease in plasma viral loads compared to unvaccinated
controls was also measured following challenge in all three groups.
This approach avoid the concern of toxicity, which may caused by using
gp120 CD4 mimic molecular by other groups
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Novel vaccine approaches
Paper 6. First-in-human phase 1 safety and immunogenicity
of an Adenovirus Serotype 26 HIV-1 vaccine vector
� In a randomized, double-blinded, placebo-controlled, dose-escalation phase1 study. Subjects received 3 injections of doses of 109, 1010, or 1011 vp of the Ad26-EnvA or placebo.
� It was shown that the Ad26 vector is safe and immunogenic in humans atall three doses.
Ad26 repreprents a very promising new generation viralvector, overcome the pre-existing immunity against Ad5vectors (Merck trail.
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A Comprehensive HIV Prevention Toolbox
Vaccine
PrEP
Harm reduction
Microbicides
Circumcision
ARV therapy
MTCT interruption
Education
CondomsPartner Reduction
Etc.Drug/alcohol
treatment
C. Dieffenbach with modification
60% protection
African Trial of
male circumcision
31% protection of
Thai vaccine trial
(canarypox/gp120)