The Novel HIV Vaccine Approaches

---- A personal Prospective

Yiming Shao

National Center for AIDS &STD Prevention and Control

China CDC
yshao08@gmail.com
 Lessons learned
 Over simplified design (1st 10 years) does not work
gp120 vaccine simply mimic HBV vaccine, using just peptide not even bother to mak
e it as a particle like the HBsAg is.

 Shift from B cell to T cell vaccine (2nd 10 years) is not right

The mainstream research stop nAb vaccine too early and shift to the CMI vaccine to
o 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 more immunogeni
c 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 natural infection
. Business as usual approach is not work for AIDS vaccine
 Statistics of the 190 HIV vaccine clinical trials
non-replication

DNA vaccine vector va Peptides v othors

Gp120 vaccine
（ 23 ） ccine （ 8 eccine 1 （ 19 ）
（ 50 ）
7） 1）

Replicating
(3)

Ad MVA NYVAC ALVAC Others

（2 （2 （3） （ 31 ） (7 ）
3） 0）

(84)
Insanity: doing the same thing over and over again and expecting dif
rent results.
 Major scientific challenge to AIDS vaccine
Examples in nature: HBV HIV
Infection after sera conversion minority all
Disease after infection minority majority
Mortality 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 induce
good protective immunity in natural infection.
Conclusion:
In evolution, human immune system is not strong enough
to control HIV infection
The Key to a successful HIV Vaccine
To design a novel vaccine, which can re-engineer the human
immune system overcoming the inherited weakness and
acquiring the ability to block or control HIV infection .
HIV-2/HIV-1 Envelope Glycoprotein Chimeras
to Detect Epitope-specific Nabs
 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%

LD

The CD4 binding surface on gp120 is -23

42%
• functionally conserved, structurally stable and spatially accessible
-15/-3
-24
• one of the major vulnerabilities of HIV
-17
• can serve as a very attractive target for AIDS vaccine
-19/20/21

T. Zhou, L Xu, B. Dey, et al. Nature, 2007, 445:732-6

 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 intercourse i
n
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.
Rationale of the allogeneic-HIV-1-HSP70 Vaccine
HIV Virion

HLA-I * HLA II * HIV gp120 HSP70 **

KIR CD8 TCR CD4 CCR5 CD40

- NK cells, DC, Macrophages

T and Bcells, -
+

Peptide
 chain
 2M
Dextran
Backbone

Biotin *Arthur et al 1992 (more HLA than HIVgp120) TCR

Avidin
**Gurer et al 2002 (similar amount of HSP70 as viral pol protein)
CD8 + T cells
 Relationship Between Poxvirus Replication
Competence and Safety and Immunogenicity
Live, non-replication Live, poxvirus-based vaccine Live, replication
competent poxvirus- with self-limiting replication competent poxvirus-
based vaccine capacity based vaccine

Infection without Infection with immune- Infection with virus

replication controlled replication replication and spread

Immunogenicity
Safety
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.)
Phase I/II Clinical trials of recombinant VTT vaccines
for HAV , HBV, EBV, and Measles in children
 Phase I Clinical Trial Design of DAN Prime
Replicative Tiantan (rTV) Boost Strategy

Phase I trail application to SFDA in 2005

Approved for Phase Ia in 2007, Phase Ib in 2008

Phase Subjects Vaccine Test Period

Ia 12 rTV 24W
Ib 36 3DNA+rTV 36W
Protection against pathogenic SIV in
rhesus macaques
Monkeys Protection ( >3
Vaccine Strategy log suppression of viral
load)

Live attenuated 74/78 (95%)

All other strategies 18/256 (7%)

Koff, W. etal, Nature Immunology 2005

 The Development of Live Attenuated EIAV Vaccine

LN40 EIAV WT
(Pathogenic Strain) (Field Isolate)
16 Passages in
Horse

117Passages in Donkey

D510 (Highly Pathogenic)

123Passages in
Donkey Leukocyte

DLV (Attenuated Vaccine)

8 lentiviruses,
12Passages in Fetal
2 Vaccines: Donkey Dermal Cell

EIAV 1975, China DDV (Attenuated Vaccine)

FIV 2002, USA
 0 1 2 3 4 5 6 7 8 9 kb
体内毒力 ( 驴 ) 代次
EIAV LTR gag env LTR
基因组
1
pol S2
tat1 tat2
100%

20
  
29 代
67%
40 代  
40
  
52 代 58%
60 代 60
69 代 
50%
78 代
80

91 代  
8%
100
106 代 

120
基因突变 tat gag pol S2 env

重要突变 1 3 2 3 7

关键突变 0 0 1 0 3
Comparison of humoral immune responses induced by the attenuated vaccin
e, the cloned attenuated vaccine and DNA/rVaccinia vaccines
Novel vaccine approaches

Paper 1. Aaron Diamond AIDS Research 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 thr

ough in vivo electroporation induced significantly improved immune
responses with stronger magnitude and wider bredth in human subjec
ts as demonstrated in the phase I trial
Novel vaccine approaches
Paper 2. University of Pennsylvania
Analysis of DNA compared to Ad5 vaccination, as single a
nd mixed modalities, demonstrates robust induction of cel
lular immune responses in macaques
• They have previously reported dramatic increases in immune responses i
nduced by DNA vaccines delivered by electroporation (EP), resulting in i
mproved control of viral replication following a SIVmac251 challenge.
• This time they will show us some new data that subsequent Ad5 immuni
zations failed to boost responses while the DNA+EP group generated T c
ell responses with a very very high magnitude. The T cell response was h
igher in the DNA+EP group compared to the Ad5 group .
• This results is very encouraging. We have few reports so far that DNA va
ccination can induce immune responses comparable to those induced by
viral vectored vaccine candidates.
Novel vaccine approaches
Paper 3. FIT Biotech, University of Tartu, CEA / Division of Im
muno-Virology
Efficacy study of a T-cell-based DNA vaccine delivered by intr
adermal 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 the vaccinated anim
als.

These above 3 approaches may overcome the weakness of DNA vaccine in deli
very to human cells, a similar problem in gene therapy
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.
Novel vaccine approaches
Paper 5. Karolinska Institutet
Impact of in vivo CD4 binding during HIV-1 Env trimer immu
nizations of rhesus macaques
• Rhesus macaques were immunized with wt trimers or CD4 binding defective tri
mers.
• Antibodies against the co-receptor binding site were elicited in animals immuniz
ed with wt trimers, but not in animals immunized with the CD4-binding defectiv
e mutants. Differences in the quality of the in vitro neutralizing antibody respons
e were observed.
• Elimination of the Env-CD4 in vivo interaction region did not affect vaccine-ind
uced Env-specific T cell responses or levels of total elicited binding 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
Novel vaccine approaches

Paper 6. First-in-human phase 1 safety and immunogenicity of an A

denovirus Serotype 26 HIV-1 vaccine vector

• In a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 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 at all three d
oses.

Ad26 repreprents a very promising new generation viral vector, ove

rcome the pre-existing immunity against Ad5 vectors (Merck trail
.
Global collaboration is the key to an AIDS vaccine
A Comprehensive HIV Prevention Toolbox

60% protection 31% protection of

African Trial of Thai vaccine trial
(canarypox/gp120)
male circumcision

Vaccine Microbicides

PrEP Education
Partner Reduction Condoms
ARV therapy
MTCT interruption
Circumcision
Circumcision
Drug/alcohol
Harm Etc.
Harmreduction
reduction treatment
C. Dieffenbach with modification