1. Vaccini come paradigma di ricerca
al servizio della salute globale
Rino Rappuoli
Scienza e industria
Ricerca e innovazione in biomedicina
Università Bocconi,
Milano, 27 novembre 2013

2. people live longer

3. 3

4. 4

5. 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

6. 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

7. 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

8. Vaccination, the most effective medical
intervention ever introduced
 So far saved >700 million disease cases,
>150 million deaths
 2011-2020 vaccines will save
25 million deaths
2.5 million/year
7000/day
300/hour
5/min
WHO Global Action Plan
http://www.who.int/immunization/global_vaccine_action_plan/GVAP_doc_2011_2020/en/index.html)
8

9. From Jenner to Pasteur to Hilleman
Isolate
Inactivate
Inject the
microorganism causing disease

10. During the last 30 years, several new technologies made
possible vaccines that were previously impossible

11. During the last 30 years, several new technologies made
possible vaccines that were previously impossible

12. Meningococcal disease
Caused by Neisseria meningitidis capsular serogroups A,
Death
B, C, Y, W135
Severe
disability
Dreaming the olympic games
like Pistorius
Tragedies
covered by media

13. During the last 30 years, several new technologies made
possible vaccines that were previously impossible
Conjugate vaccines

14. Capsular polysaccharides & Conjugates
Haemophilus influenzae type B (Hib)
Capsule
Pneumococcus
Meningococcus
Group B streptococcus
Capsule
Polysaccharide
Conjugate

15. MenC Conjugate Vaccine (red) Induced high level of Bactericidal Antibodies in
Infants. Plain Polysaccharide (blue) was a poor Immunogen

16. Conjugate vaccines for Meningococcus C
eliminated the disease in the UK
Laboratory Confirmed Cases of Serogroup C Meningococcal Disease
(England & Wales)
Since the introduction of the UK MenC vaccine in 1999
Vaccine
>13,000 cases prevented
> 1,300 deaths prevented
>2,750 permanent sequelae prevented
Week No. (totals from mid-year)

17. Meningococcus B capsule is a self antigen
and cannot be used for vaccination

18. During the last 30 years, several new technologies made
possible vaccines that were previously impossible
Reverse Vaccinology

19. Reverse vaccinology
a genomic approach to vaccine discovery
Express
recombinant
proteins
600 potential vaccine candidates
identified
350 proteins successfully expressed
in E.coli
In silico vaccine
candidates
91 novel surface-exposed
proteins identified
28 novel proteins
have bactericidal
activity
VACCINE CANDIDATES

20. 4CMenB Vaccine Composition
 Three protein antigens (two fusion proteins and one single polypeptide)
 Outer Membrane Vesicle (OMV) component (NZ PorA is P1.4)
LPS
PorA
OMV
Class 4
NadA
fHBP
NHBA
Class 5
PorB
 4CMenB is a suspension for injection
Dose
NHBA-
fHbp-
GNA1030
GNA2091
NadA
OMV
0.5ml
50 µg
50 µg
50 µg
25 µg
Al3+
0.5 mg

21. Clinical Development
Immunogenicity, Persitance, Concomitant administration, Tolerability
Infants and children 2
months to <2 years of age
5850
•5850 received at least 1 dose of
BEXSERO
•3285 received booster dose in second
year of life
Children 2 to 10 years of
age
•250 were included
250
1703
Adolescents and adults ≥11 years of
age
•
1703 were included
*Evaluated in 13 studies including 9 randomized controlled clinical trials.

23. MenB Vaccine UK media
CHMP positive opinion
16 November 2012

24. Towards a meningitis free world
The first vaccine lot was released this week
Now we can eliminate meningococcal meningitis

25. Reverse vaccinology allowed us to target many
pathogens that were difficult or impossible before
Including SUPERBUGS
4CMenB first genome derived
vaccine
t!!!!
stan s
i
res ccu
c
ioti yloco
ntib aph
A
coli ile
t
S
E. fic
s
. dif mona
C
o
eud
Ps
!!!
GS
BU
ER
UP
S
Group B Streptococcus Yersinia pestis
Group A Streptococcus
Chlamydia
Malaria

26. During the last 30 years, several new technologies made
possible vaccines that were previously impossible
Adjuvants

27. MF59: oil-in-water adjuvant licensed with seasonal trivalent (1997) and
pandemic monovalent vaccine
Progenitor of other oil-in-water based adjuvants
160nm
 Oil-in-water emulsion adjuvant
licensed for use in seasonal
influenza vaccine FLUAD→*
since 1997
• More than 200 million
oil
commercial doses distributed
 >120 Clinical studies, >200,000
subjects
• No safety signals in either Safety
MF59 adjuvant emulsion
shown also in pregnant women
Antigens
 Pediatric studies and efficacy
trial in >3,000 subjects
SPAN 85
TWEEN 80
Licensed for 2009 A(H1N1)
pandemic vaccine (all ages)

28. MF59 increases efficacy of influenza vaccine in
children from 43 to 86%
cci
Va
1.0
ne
59
MF
+
Vaccine efficacy
vs. non-influenza control
0.8
0.6
ci
ac
V
0.4
ne
0.2
Vaccine also showed satisfactory
safety profile:
•Increased local reactogenicity
•No increase in serious adverse
experiences vs. control
0.0
–
0.2
Fluad
–
0.4
–
0.6 0
TIV
20
40
60
80
100
120
140
Days post-second dose
Vesikari T, et al. NEJM.
160
180
200
220

29. During the last 30 years, several new technologies made
possible vaccines that were previously impossible
Synthetic biology
 Synthetic seeds
 Self Amplifying
Messenger RNA
(SAM)

30. Influenza, eggs & cell culture
time to retire the eggs?
TechnoIogy of 1930’s
Cell culture, licensed by the FDA in 2012

31. A synthetic Influenza Vaccine Seed in 5 days
shipping information instead of viruses

32. During the last 30 years, several new technologies made
possible vaccines that were previously impossible
What do we do with all
these technologies?

33. 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

34. Vaccines for every age
R.Rappuoli, C. Mandl, S: Black , E. De Gregorio
Nature Reviews Immunology | November 2011; doi:10.1038/nri3085

36. 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 for
neglected 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

37. 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

38. Jobs, investments, brains
1992
Jobs
2006
2013
234
1100
2000
Investments
Investments in R&D
------280M---------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