The Novel HIV Vaccine Approaches

---- A personal Prospective

Yiming Shao

National Center for AIDS &STD Prevention and Control China CDC

yshao08@gmail.com

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

Lessons learned

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.

Major scientific challenge to AIDS vaccine

Examples in nature: HBV HIVInfection after sera conversion minority all Disease after infection minority majorityMortality after disease minority almost allObservation:• 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%

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

-15/-3

-17

-19/20/21

LD

-24

-23

42%

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 in

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.

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)

Dextran Backbone

CD8 + T cells

TCRBiotinAvidin

2 M

chainPeptide

- -+

Relationship Between Poxvirus Replication Competence and Safety and Immunogenicity

Immunogenicity

Live, non-replication competent poxvirus-

based vaccine

Live, poxvirus-based vaccine with self-limiting replication

capacity

Live, replication competent poxvirus-

based vaccine

Infection with immune-controlled replication

Safety

Infection with virus replication and spread

Infection without replication

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 PrimeReplicative Tiantan (rTV) Boost Strategy

Phase Subjects Vaccine Test Period

Ia 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

Protection against pathogenic SIV in rhesus macaques

Vaccine StrategyMonkeys Protection ( >3 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

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 16 Passages in HorseHorse

117Passages in Donkey117Passages in Donkey

123Passages in 123Passages in Donkey LeukocyteDonkey Leukocyte

12Passages in Fetal 12Passages in Fetal Donkey Dermal CellDonkey Dermal Cell

8 lentiviruses,

2 Vaccines:

EIAV 1975, China

FIV 2002, USA

LTR LTRgag

pol

env

S2

tat1 tat2

EIAV EIAV 基因组基因组

6060 代代

7878 代代

6969 代代

106106 代代

9191 代代

2929 代代

4040 代代

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

体内毒力体内毒力 (( 驴驴 )) 代次代次11

2020

4040

6060

8080

100100

120120

100%100%

67%67%

58%58%

50%50%

8%8%

5252 代代

0 1 2 3 4 5 6 7 8 9 kb

Comparison of humoral immune responses induced by the attenuated vaccine, 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 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.

Novel vaccine approaches

Paper 3. FIT Biotech, University of Tartu, CEA / Division of 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 gro

ups. Differences in anti-Gag responses may explain this observation. • Reduction of SIV-DNA copies in rectal biopsies was observed in all the vaccinated an

imals.

These above 3 approaches may overcome the weakness of DNA vaccine in delivery to human cells, a similar problem in gene therapy

Novel vaccine approachesPaper 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 approachesPaper 5. Karolinska 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 animals immunized 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 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 Adenovirus 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 doses.

Ad26 repreprents a very promising new generation viral vector, overcome the pre-existing immunity against Ad5 vectors (Merck trail.

Global collaboration is the key to an AIDS vaccine

A Comprehensive HIV Prevention Toolbox

Vaccine

PrEP

Harm reductionHarm reduction

Microbicides

CircumcisionCircumcision

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)