novel vaccine approaches (yiming shao)

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

[email protected]



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



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 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 .



HIV-2/HIV-1 Envelope Glycoprotein Chimeras to DetectEpitope-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

F-15/E-3

F-17

F-19/20/21

LD

F-24

F-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 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.



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

- -+



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



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 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



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



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



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



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 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




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.




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




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.




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




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.



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)

novel vaccine approaches (yiming shao)

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