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Nouvelles perspectives en
vaccinologie
AAEIP, Université Paris Sud, 31 Mars 2014
Claude Leclerc
DEVELOPPEMENT of HUMAN VACCINES
Live attenuated vaccines
Genetically engieneered
Purified protein or polysaccharide Killed vaccines
Smallpox, 1798 Rabies, 1885 BCG, 1927 Yellow fever, 1935 Polio (oral) Measles Mumps Rubella Adenovirus Typhoid (Ty21a) Varicella Rotavirus
Diphteria, 1923 Tetanus, 1927 Pneumococcus Meningococcus Haemophilus influenzae PRP Hepatitis B (plasma derived) Tick-birne encephalitis H. influenzae PRP conjugate Typhoid (Vi) Acellular pertussis
Typhoid 1896 Cholera, 1896 Plague, 1897
Pertussis, 1926 (killed bacteria) Influenza, 1936 Rickettsia, 1938
Polio (injected) Rabies (new) Japanese Encephalitis Hepatitis A
Hepatitis B (recombinant) Human Papilloma virus Rotavirus
18th Century
19th Century
Early 20th Century
After World War II (cellular culture)
Vaccines have been made for 36 of >400 human pathogens
Immunological Bioinformatics, The MIT press.
+HPV & Rotavirus
The different types of vaccines
Attenuated Vaccines
Killed Vaccines
Acellular sub-unit vaccines
Pertussis Diphteria Hepatitis B Tetanus
Cholera Pertussis Hepatitis A Polio
Polio Yellow fever BCG
New and improved technologies and resulting vaccines
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
New and improved technologies and resulting vaccines
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
New and improved technologies and resulting vaccines
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
New and improved technologies and resulting vaccines
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
New and improved technologies and resulting vaccines
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
Dengue epidemiology
Nature Reviews Microbiology 2010
Dengue vaccines under development
Dengue vaccines under development
Sanofi Pasteur dengue vaccine enters phase III clinical study in October 2010
The yellow fever 17D virus as a platform for new live attenuated vaccines
Worldwide map of phase II/III dengue clinical trials, and major results obtained so far in humans
Guy et al, Vaccine, 2011, 7229-7241
Lancet, Published Online, September 11, 2012
Serotype-specific and overall efficacy of CYD tetravalent dengue vaccine against virologically confirmed dengue disease
Reverse cumulative distribution of serotype-specific PRNT 50 antibody titres curves for DENV serotypes 1–4 by baseline FV-serostatus, pre-vaccination and after two and three doses of CYD-TDV (Full Analysis Set).
Vaccine, Volume 31, 2013, 5814 - 5821
sReuters, March 25, 2014
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
Schematic representation of the CSP and the RTS,S vaccine
P D. Crompton, SK. Pierce, L H. Miller J Clin Invest. 2010
Malaria cuts risk in half in late-stage trial
H Waters Nature Medicine Nov 2011
N Eng J Med 2012
Malaria cuts risk in half in late-stage trial
H Waters Nature Medicine Nov 2011
31%
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
How to discover protective
antigens?
Identification of new target antigens: impact of genomics
Whole genome sequences of most bacterial pathogens and parasites completed
E. coli K-12 B. burgdorferi B. subtilis M. tuberculosis R. prowazekii H. influenzae C. pneumoniae C. trachomatis N. gonorrhoeae S. aureus H. pylori P. horikoshü E. faecalis N. meningitidis S. epidermitis M. genitalium S. pneumoniae L. pneumophila P. falciparum S. pyogenes M. pneumoniae T. pallidum L. major P. aeruginosa T. cruzi
M. leprae P. aerophilum V. cholerae
Genomic-based vaccine development
Whole genomic sequence
Computer prediction
Expression of recombinant proteins
DNA preparation
In silico vaccine candidates
Immunogenicity testing in animal models
Vaccine development
600 potential vaccine candidates identified
350 proteins successfully expressed in E.coli
344 proteins purified and used to immunize mice
355 sera tested 91 novel surface-exposed
proteins identified 28 novel proteins have bactericidal
activity
Meningoccocal B Vaccine: A Genomic Approach
5 vaccine candidates Rappuoli et al, 2002 Clinical trials
2000 2013
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
Front Immunol 2014
Structural vaccinology
A new computational method to design epitope-focused vaccines, illustrated with a neutralization epitope from RSV
Nature 507, 201–206 (13 March 2014)
Nature 507, 201–206 (13 March 2014)
Induction of neutralizating antibodies against RSV
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
Overview of the problems and methodologies of systems vaccinology
Seminars in Immunology, 2013, 209 - 218
R Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Published online 4 November 2011
Alum adjuvants are non-cystalline gels based on aluminum oxyhydroxide (referred to as Aluminum hydroxide gel), aluminum hydroxyphosphate (referred to as aluminum phosphate gel) or various proprietary salts such as aluminum hydroxy-sulfate) Alum is used in several licensed vaccines including:
• diphtheria-pertusis-tetanus • diphtheria-tetanus (DT) • DT combined with Hepatitis B (HBV) • Haemophilus influenza B • inactivated polio virus • Hepatitis A (HAV) • Streptoccucus pneumonia • Menngococccal • Human papilloma virus (HPV)
Vaccines containing Alum Adjuvant
Dendritic cells initiate antigen-specific immune responses
• most efficient of all APCs • high MHC class I, II & costimulators • efficient cross presentation • stimulate naïve T cells (CD4, CD8)
All immunization strategies must target DCs
Initiate Ag-specific immune responses
Multiple inducers of DC maturation
Immature DC Mature DC
various T cell responses
Microbial products / TLR ligands Viral products Inflammatory cytokines Signaling receptors
Antigen-presenting cells serve as the bridge between innate and antigen-specific responses
2003, 2, 727-735
Rappuoli, CW. Mandl, S Black & E De Gregorio Nature Reviews Immunology Nov 2011
Vaccine adjuvants
Innate immune responses
Innate Lymphoid Cells (ILC)
T cell differentiation pathways
Coomes S M et al. Open Biol. 2013;3:120157 ©2013 by The Royal Society
Therapeutic vaccines
for chronic infections or cancers
Cancer, a worldwide burden
1st cause of mortality in France
In Europ, in 2012: - 1.75 million deaths from cancer - 3.45 million new cases of cancer
In the world, in 2012: - 8.2 millions deaths - 14 million new cases diagnosed
Cancer, a cell disease
uncontrolled proliferation
Tumor
Surgery
Chimiotherapy Radiotherapy
Anti-angiogenic drugs
Immune responses can control the growth of tumor cells
The immunosurveillance theory
“It is by no means inconceivable that small accumulations of tumour cells may develop
and because of their possession of new antigenic potentialities provoke an effective immunological reaction, with regression of
the tumor and no clinical hint of its existence”
British Med Journal, April 1957
Burnet
Tumor specific/associated antigens
Overexpressed self antigens
Differentiation antigens
Mutated self antigens
Non self oncoviral antigens
Altered self antigens: Abnormal post-
translational/transcriptional modification:
underglycosylation
The concept of therapeutic anti-cancer vaccines
Induction of specific immune responses against tumor specific/associated antigens to kill tumor cells or prevent their growth without affecting normal cells
Tumor vaccines - Whole tumor cells: + BCG or DETOX, e.g. Melacine vaccine (cell lysates), CancerVax
( irradiated melanoma cell lines), M-Vax (hapten-treated autologous cells) and gene-modified, irradiated tumor cells (GM-CSF)
- Tumor antigens: MAGE-1, MAGE-3, MART-1/Melan-A, tyrosinase, gp100, MUC-1,
CEA, etc. - Peptide vaccines: mutated ras, mutated p53, Her-2/neu, MART -1, gp100, MUC-1 - Heat shock proteins - DNA vaccines - Dendritic cell vaccines
Response rate = 3. 8%
Current human cancer vaccines show very low objective clinical response rate
Rosenberg, Yang & Restifo Nature Med 10:909 (2004)
Response rate = 3. 8%
Current human cancer vaccines show very low objective clinical response rate
Rosenberg, Yang & Restifo Nature Med (2004)
Benefit of passive immunotherapy (antibodies)
in cancer patients Lack of efficacy of most
current therapeutic cancer vaccines
Problems
Tumor derived antigens are weakly immunogenic
Need for better adjuvants or immunisation strategies
Dendritic cells initiate antigen-specific immune responses
• most efficient of all antigen-presenting cells
• stimulate naïve T cells (CD4, CD8)
All immunization strategies must target DCs
An Approach to Initiating Immunity to Cancer: Dendritic Cells Loaded with Tumor Antigens ex vivo
DC precursors expanded immature DCs
add disease- related antigens
maturing DCs presenting antigen(s)
Tumor- specific T cells
responding to
dendritic cells
2010: FDA panel passes first cancer vaccine
Original Article Sipuleucel-T Immunotherapy for Castration-
Resistant Prostate Cancer Philip W. Kantoff, M.D., Celestia S. Higano, M.D., Neal D. Shore, M.D., E. Roy
Berger, M.D., Eric J. Small, M.D., David F. Penson, M.D., Charles H. Redfern, M.D., Anna C. Ferrari, M.D., Robert Dreicer, M.D., Robert B. Sims, M.D., Yi Xu, Ph.D., Mark
W. Frohlich, M.D., Paul F. Schellhammer, M.D., for the IMPACT Study Investigators
N Engl J Med Volume 363(5):411-422
July 29, 2010
Source: www.provenge.com/
Provenge clinical trials : prostate cancer
Source: www.provenge.com/
Provenge clinical trials : prostate cancer
Cancer vaccine pipeline
Problems
Tumor derived antigens are weakly immunogenic
Need for better adjuvants or immunisation strategies
CD8+ T cell
CD4+ T cell
Dendritic cell
Induction of optimized T cell responses by in vivo dendritic cells targeting
Antigen targeting
Maturation signals 2
1 Adjuvant
CyaA: a new proteinic vector targeted to dendritic cells
Bordetella pertussis
Dermonecrotic Toxin
BrkA FHA
TCF FIM
TCT
Pertussis Toxin
cAMP
Pertactin
Adenylate cyclase Toxin
DendriticCell
CD11b/CD18
AC domain
RTX domain
1 400 1706
InternalizationEndosomes
Cytosol
CyaA binds to CD11b allowing efficient targeting
to dendritic cells
Guermonprez et al, J. Exp. Med, 2001
Adenylate cyclase (CyaA)
Recombinant CyaA
+
Activation of CD8+ Cytotoxic T lymphocytes
Dendritic Cell ϕ
CD11b/CD18
Antigen
Th CD4+ MHC-II
endosomes
lysosomes
ϕ ϕ
MHC class II presentation
Activation of CD4+ Helper T lymphocytes
MHC class I presentation
Endoplasmic Reticulum
CTL CD8+ MHC-I/β2
ϕ Translocation Endocytosis
Antigens grafted in CyaA are delivered to both MHC class I & MHC class II presentation pathways
Immunisation in mice and non-human primates by
recombinant CyaA carrying a variety of antigens (such as
from M. tuberculosis or HIV) stimulates strong CTL and Th1
responses, even in the absence of adjuvant.
Préville et al, Cancer Res, 2005, Mascarell et al, J. Virol 2005, Majlessi et al, Inf Immun, 2005, Hervas-Stubb et al, Inf Immun, 2006, Mascarell et al, Vaccine 2006, Berraondo et al,
Cancer Res, 2007, Fayolle et al, Vaccine 2010.
CyaA: a new proteinic vector targeted to dendritic cells
80
HPV infection life cycle Few months to few years Up to 20 years
Goodman A., Wilbur D. C.
Human papilloma virus
��� - The HPV E6 and E7 oncoproteins are expressed throughout the replicative cycle of the virus and are necessary for the onset and maintenance of malignant transformation.��� - HPV E6 and E7 antigens are potential targets for specific
immunotherapy.
Rational
MHGDTPTLHEYMLDLQPETTDLYCYEQLN
CyaAE5
GQAEPDRAHYNIVTFCCKCDSTLRLCVQSTHVDIRTLEDLLMGTLGIVCPICSQKP
CyaA-E7∆30-42
Catalytic domain
224 235 319 320
1 400 1706
LQ
LQ
Recombinant CyaA carrying E7 from HPV16
GMP batch produced in recombinant E. coli
Therapeutic vaccination with recombinant���HPV16-E7 CyaAs eradicates established tumors
No treatment CyaA-OVA
0 500
1000 1500 2000
0 10
5/5 10/10
0/10
20 30 40 50 60 70 80 90 0 500
1000 1500 2000
CyaA-HPV16E7∆30-42
- Graft of TC-1 cells at day 0
- At day 10, one injection of:
- 50 µg of CyaA-E7 or of control CyaA-OVA
Preville et al, Cancer Res. 2005; Berraondo, K. et al. Cancer Res. 2007
A therapeutic vaccine candidate against HPV chronic infection and/or cervical cancer
Clinical trials started in 2010
0 102030405060708090
0
500
1000
1500
2000
0 102030405060708090
0
500
1000
1500
2000
0 102030405060708090100
0
20
40
60
80
100
0 5 10 15 20 25 30 35
0.0
0.2
10
20
daysdays days
CyaAE5 HPV16E7∆30-42 CyaAE5 CysOVA
Controls
One injection at Day 10
CyaAE5 HPV16E7∆30-42
Préville et al, Cancer Res, 2005
http://www.genticel.com
ProCervix - Phase 2 Clinical Trial