La vaccinazione Ilfondamento della pratica immunologica Rino Rappuoli Firenze 12 Novembre 2016
Some history of human evolution 55 years gained since 1700 35 years gained since 1900 2
In 1900 in the USA life was short
In 1900 in the USA people died of infectious diseases Infectious Diseases Infectious Diseases Diphtheria (40million prevented) Diphtheria (40million prevented) Measles (35 million prevented) Measles (35 million prevented) Smallpox ... Smallpox ... Non Communicable Diseases Ischemic Heart Disese Stroke Cancer Diabetes Alzheimer .....
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
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Conjugate vaccines
Capsular polysaccharides & Conjugates Haemophilus influenzae type B (Hib) Capsule Capsule Pneumococcus Polysaccharide Meningococcus Group B streptococcus Conjugate
MenC Conjugate Vaccine (red) Induced high level of Bactericidal Antibodies in Infants. Plain Polysaccharide (blue) was a poor Immunogen
Meningococcus B capsule is a self antigen and cannot be used for vaccination
Reverse Vaccinology and a vaccine for Meninigococcus B
Reverse Vaccinology A genomic approach for a Meningococcus B vaccine 600 potential vaccine candidates identified Express recombinant proteins 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
Reverse Vaccinology Craig Venter (May 11, 2001)
MenB, first vaccine to receive breakthrough therapy designation by FDA Princeton, USA London, UK Since september 1 st 2015 all newborns in the UK are vaccinated with MenB vaccine
Seguenay-Lac-Saint-Jean, 2014 Vaccination of the entire population from 2 months to 20 years of age • 43,740 people vaccinated between May 5 and 17 June 2014 • 12,332 followed with active surveillance • 14-15 % fever in less than 2 years (less than expected but high use of antipyretics ) • 2 convulsions (6 expected) • 99% willing to receive 2 nd dose • Active surveillance has not identified any severe problem and confirmed significant frequency of local pain, fever (less than expected) and general malaise . no invasive menB cases observed among the 47,115 vaccinated ages 2 mos-20 years, crude VE=100% De Serres et al, BIBLIOTHEQUE ET ARCHIVES NATIONALES DU QUEBEC, LIBRARY AND ARCHIVES CANADA . ISBN: 978-2-550-71345-6 (FRENCH PDF), ISBN: 978-2-550-71653-2 (PDF ), c Gouvernement du Quebec (2014) , http://www.inspq.qc.ca. Presentation by G. De Serres, at Feb 2016 ACIP meeting.
Real efficacy from the field 83% effectiveness and 94% efficacy during the first 10 months in the UK 17
The largest petition ever in the UK is for MenB vaccination (before Brexit) • More than 820 000 people have backed a campaign for all children up to the age of 11 years to receive GlaxoSmithKline’s Bexsero , which is currently used as part of routine vaccination for babies born since May 1, 2015, with doses at 2 months, 4 months, and a booster at 12 months. Faye’s story – The Lancet Infectious Diseases 16, pg 385, April 2016
Towards a meningitis free world Now we can eliminate meningococcal meningitis Reverse Vaccinology can also provide vaccines for Antibiotic Resistant bacteria (superbugs!!!) Staphylococcus E. coli C. difficile Pseudomonas Group A Streptococcus
Reverse Vaccinology 2.0: human immunology instructs vaccine antigen design Rappuoli, Bottomley, D’Oro, Finco, De Gregorio JEM April 2016
Structural Vaccinology Structure-based antigen design
Structural Vaccinology the RSV example Pre-fusion Post-fusion
Synthetic biology • Vectors • Synthetic seeds • Self Amplifying Messenger RNA (SAM)
Viral vectors Ebola Ebola 24
Adjuvants
MF59 increases efficacy of influenza vaccine in children from 43 to 86% 160nm 9 5 F M + e oil n i c 1.0 c a V 0.8 vs. non-influenza control e 0.6 n MF59 adjuvant emulsion i c c Vaccine efficacy a V 0.4 Antigens SPAN TWEEN 80 85 0.2 Vaccine also showed satisfactory 0.0 safety profile: – • Increased local reactogenicity 0.2 • No increase in serious adverse Fluad – experiences vs. control 0.4 TIV – 0.6 0 20 40 60 80 100 120 140 160 180 200 220 Days post-second dose Vesikari T, et al. NEJM.
Three breakthrough vaccines in 2015 Vaccines continue to serve our society First Malaria vaccine licensed AS01 adjuvant Zoster vaccine 97% efficacy in the elderly AS01 adjuvant Ebola vaccine 100% efficacy VSV Viral vector 27
How can these technologies help our society?
Vaccines can do more for our society Great job! R.Rappuoli, C. Mandl, S: Black , E. De Gregorio Nature Reviews Immunology | November 2011; doi:10.1038/nri3085
Vaccines can do more for our society ! t e g r a t t x e N R.Rappuoli, C. Mandl, S: Black , E. De Gregorio Nature Reviews Immunology | November 2011; doi:10.1038/nri3085
Vaccines can do more for our society ! t e g r a t t x e N Great job! R.Rappuoli, C. Mandl, S: Black , E. De Gregorio Nature Reviews Immunology | November 2011; doi:10.1038/nri3085
Vaccines for today’s society
In low income countries life is still very short
In poor countries people die from Infectious Diseases Vaccines can make a big difference
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) New name: GSK Vaccine Institute for Global Health (GVGH) 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 Shighella vaccine Phase I 2014
The Grand Convergence To close the health gap between poor and rich countries 36
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