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

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–0.2

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0.6

0.8

1.0

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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