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Vaccini come paradigma di ricerca al servizio della salute globale
Rino Rappuoli
Scienza e industriaRicerca e innovazione in biomedicina
Università Bocconi, Milano, 27 novembre 2013
people live longer
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The unfinished cathedral
In Siena, an unfinished cathedral is the largest existing monument to Infectious Diseases, standing reminder of a flourishing economy and culture wiped out forever in just three months by the 1348 PLAGUE
Smallpox: An Ancient and Deadly Disease
Daniel Bernoulli (mathematician and physician; 1700 – 1782) estimated that, in
Europe, there were, on average, ca. 600,000 deaths each year from Smallpox.
European population ca. 80M
Every year 1 person every 140 died from the disease
Smallpox: An Ancient and Deadly Disease
- 1707 36% of Island population died
- 1709 14,000 died in Paris
- 1753 20,000 died in Paris
- 1768 60,000 died in Naples
WHO Global Action Plan http://www.who.int/immunization/global_vaccine_action_plan/GVAP_doc_2011_2020/en/index.html)
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So far saved >700 million disease cases, >150 million deaths
2011-2020 vaccines will save
25 million deaths
2.5 million/year7000/day
300/hour 5/min
Vaccination, the most effective medical intervention ever introduced
From Jenner to Pasteur to Hilleman
Isolate Inactivate Inject the microorganism causing disease
During the last 30 years, several new technologies made possible vaccines that were previously impossible
During the last 30 years, several new technologies made possible vaccines that were previously impossible
Meningococcal disease
Tragedies covered by media
Severedisability
Death
Caused by Neisseria meningitidis capsular serogroups A, B, C, Y, W135
Dreaming the olympic games like Pistorius
During the last 30 years, several new technologies made possible vaccines that were previously impossible
Conjugate vaccines
Haemophilus influenzae type B (Hib)
Pneumococcus
Meningococcus
Group B streptococcus
Capsular polysaccharides & Conjugates
Capsule
Capsule
Polysaccharide
Conjugate
MenC Conjugate Vaccine (red) Induced high level of Bactericidal Antibodies in Infants. Plain Polysaccharide (blue) was a poor Immunogen
Conjugate vaccines for Meningococcus Celiminated the disease in the UK
Laboratory Confirmed Cases of Serogroup C Meningococcal Disease (England & Wales)
Week No. (totals from mid-year)
VaccineSince the introduction of the UK MenC vaccine in 1999
>13,000 cases prevented> 1,300 deaths prevented
>2,750 permanent sequelae prevented
Meningococcus B capsule is a self antigen and cannot be used for vaccination
During the last 30 years, several new technologies made possible vaccines that were previously impossible
Reverse Vaccinology
Reverse vaccinologya genomic approach to vaccine discovery
In silico vaccine candidates
Express recombinant
proteins
VACCINE CANDIDATES
600 potential vaccine candidates identified
350 proteins successfully expressedin E.coli
91 novel surface-exposedproteins identified
28 novel proteinshave bactericidal
activity
4CMenB Vaccine Composition
Three protein antigens (two fusion proteins and one single polypeptide)
Outer Membrane Vesicle (OMV) component (NZ PorA is P1.4)
Dose NHBA-GNA1030
fHbp-GNA2091 NadA OMV Al3+
0.5ml 50 µg 50 µg 50 µg 25 µg 0.5 mg
4CMenB is a suspension for injection
Class 5
PorA
Class 4
PorB
LPS
OMV
fHBP NadA NHBA
Clinical Development
Infants and children 2 months to <2 years of age
•5850 received at least 1 dose of BEXSERO
•3285 received booster dose in second year of life
Adolescents and adults ≥11 years of age
• 1703 were included
Children 2 to 10 years of age
•250 were included
*Evaluated in 13 studies including 9 randomized controlled clinical trials.
Immunogenicity, Persitance, Concomitant administration, Tolerability
5850
1703
250
MenB Vaccine UK media CHMP positive opinion 16 November 2012
Towards a meningitis free world
The first vaccine lot was released this weekNow we can eliminate meningococcal meningitis
Reverse vaccinology allowed us to target manypathogens that were difficult or impossible before
Including SUPERBUGS
Antibiotic resistant!!!!
Staphylococcus
E. coli
C. difficile
Pseudomonas
SUPERBUGS!!!
Group B Streptococcus
Group A Streptococcus Chlamydia MalariaYersinia pestis
4CMenB first genome derived vaccine
During the last 30 years, several new technologies made possible vaccines that were previously impossible
Adjuvants
MF59: oil-in-water adjuvant licensed with seasonal trivalent (1997) and pandemic monovalent vaccineProgenitor of other oil-in-water based adjuvants
MF59 adjuvant emulsion
oil
SPAN 85 TWEEN 80Antigens
160nm Oil-in-water emulsion adjuvant licensed for use in seasonal influenza vaccine FLUAD→* since 1997
• More than 200 million commercial doses distributed
>120 Clinical studies, >200,000 subjects
• No safety signals in either Safety shown also in pregnant women
Pediatric studies and efficacy trial in >3,000 subjects Licensed for 2009 A(H1N1)
pandemic vaccine (all ages)
Fluad
TIV
–0.6
–0.4
–0.2
0.0
0.2
0.4
0.6
0.8
1.0
Va
cci
ne
eff
icac
yv
s. n
on
-in
flu
enza
co
ntr
ol
0 20 40 60 80 100 120 140 160 180 200 220
Days post-second dose
Vesikari T, et al. NEJM.
MF59 increases efficacy of influenza vaccine in children from 43 to 86%
Vaccine also showed satisfactory safety profile:
•Increased local reactogenicity•No increase in serious adverse
experiences vs. control
Vaccine + MF59
Vaccine
During the last 30 years, several new technologies made possible vaccines that were previously impossible
Synthetic seeds
Self Amplifying Messenger RNA (SAM)
Synthetic biology
Influenza, eggs & cell culturetime to retire the eggs?
TechnoIogy of 1930’s
Cell culture, licensed by the FDA in 2012
A synthetic Influenza Vaccine Seed in 5 daysshipping information instead of viruses
During the last 30 years, several new technologies made possible vaccines that were previously impossible
What do we do with all these technologies?
Vaccines have been developed for children With an aging society, we need a new model for health care
R.Rappuoli, C. Mandl, S: Black , E. De Gregorio Nature Reviews Immunology | November 2011; doi:10.1038/nri3085
Vaccines for every age
R.Rappuoli, C. Mandl, S: Black , E. De Gregorio Nature Reviews Immunology | November 2011; doi:10.1038/nri3085
Vaccines against poverty An Institute to address the gaps in vaccine development
In the recent past, no mechanism was in place to develop vaccines needed only in developing countries
Novartis Vaccines Institute for Global Health (NVGH)A new non-profit initiative
to develop effective and affordable vaccines forneglected infectious diseases of developing countries
Located in Siena , Italy
Legal entity started in Feb 2007
Allan Saul hired as CEO Sept 2007
Inauguration Feb 22, 2008
Typhoid vaccine licensed to BioE post phase II, June 2013
Master Program in Vaccinology & Pharmaceutical Clinical Development:
•Has reached so far 24 countries of the developing world
•70% of the former students are actively working in the vaccinology field
•Former students are followed for 5 y
Jobs, investments, brains
1992 2006 2013
Jobs 234 1100 2000
Investments ------280M-----Investments in R&D -----890M-----
People 45% of our collaborators are women 45% are graduated employees
40% are less than 35 years old Collaborators come from 43 different countries