Innovations in Vaccinology

Innovations in VaccinologySymposium on Innovation in Vaccine R&DIAVI and Imperial College London Rino Rappuoli London, September 5th 2012

20th Century VaccinesInitiated by Jenner, Developed by Pasteur

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

We need new vaccines to address the major health challenges of the 21st century 1 21st century society, “aging society“ Emerging 2 infections 3 Poverty

people live longer Which factors influenced this change?

Crimmins et al. Attribute the Increase of LifeExpectancy to the Conquest of Infectious Diseases Reduced infant mortality Less IncreasedInfectious LifeDiseases Expectancy Reduced Mortality in the Less Elderly inflammation

Life Expectancy is outpacing PredictionWith 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 for poverty, emerging infections and special populations R.Rappuoli, C. Mandl, S: Black , E. De Gregorio Nature Reviews Immunology | November 2011; doi:10.1038/nri3085

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

Glyco-conjugation improves the immunogenicity of polysaccharides Many bacteria have a capsular polysaccharide Non immunogenic polysaccharide immunogenic conjugate

CRM197-based conjugate vaccines

How conjugates engage T cells

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

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

Reverse Vaccinology Allowed the Identification of Novel MenB AntigensBased on the genome sequence of MC58, 600 ORFs ~350 proteins successfully expressed inthat potentially encoded novel surface exposed or E.coli, purified, and used to immunize miceexported proteins were identified 1 IHT-A 2,200,000 100,000 2,100,000 200,000 2,000,000 300,000 expression IHT-C 1,900,000 400,000 and 1,800,000 purification 500,000 1,700,000 IHT-B 600,000 purified proteins 1,600,000 700,000 1,500,000 800,000 1,400,000 900,000 1,300,000 1,000,000 1,200,000 1,100,000 immunizations Testing for fHbp NadA NHBA bactericidal variant 1 activity Pizza M. et al. Science 2000

Reverse vaccinology allowed us to target manypathogens that were difficult or impossible beforeIncluding SUPERBUGS Group B StreptococcusGroup A StreptococcusPneumococcus Chlamydiatrachomatis and PneumoniaeTuberculosis GonococcusMalaria Porphyromonas gingivalis Yersinia pestis

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

MF59: An established adjuvant in a European-licensed seasonal trivalent vaccine Oil-in-water emulsion adjuvant licensed for use in seasonal influenza vaccine 160nm FLUAD* since 1997 • More than 100 million commercial doses distributed Adjuvanted vaccine provides oil heterologous responses to drifted strains >120 Clinical studies, >200,000 subjects • No safety signals in either pharmacovigilance database or meta- MF59 adjuvant emulsion analysis of clinical trial database with 6 month subject follow-up (filed with CBER) Antigens SPAN 85 TWEEN 80 Pediatric studies and efficacy trial in 3,000 subjects*FLUAD is a registered trademark of Novartis. FLUAD is not licensed in the Unites States.FLUAD is recommended for active prophylaxis of influenza in the elderly

MF59. more CD4+ T cells, more neutralizing (MN) antibodies 1000 A/VN/11194/04 MN- GMT Non-Adj-15 * MF59-7.5 MF59-15 * 100 *MN * * 1:40 10 1 22 43 130 202 223 382 * H5-CD4+ (in 106 tot CD4) 1000 750 * *CD4+ 500 * 250 0 1 22 43 130 202 223 382 days Galli et al, Proc Natl Acad Sci USA 2009

Frequency of H5N1- memory B cells significantly increase after heterologousboost only in people previously primed with MF59-adjuvanted H5N3 vaccine Unprimed H5N3 primed MF59-H5N3 primed Percentage of memory B cells 20 20 20 9.2 12 15 15 15 10 10 10 4.1 3.6 3.6 3.6 3.0 2.9 2.4 5 5 5 1.2 0.7 0.8 0 0 0 0 22 43 202 0 22 43 202 0 22 43 202 Galli et al, Proc Natl Acad Sci USA 106 (19): 7962-7967, 2009

An universal vaccine for avian Flu (H5N1) By day 7 post-boost most of subjects have already protective neutralizing antibody titers against all virus strains 10000 Homologous H5N1 – Clade 1 1000 Heterologous H5N1 – Clade 2.2 Heterologous H5N1 – 100 With MF59 Clade 2.3Protectivetiter (1:40) Heterologous H5N1 – Clade 2.1 10 w/o MF59 1 6-8 years Priming with H5N3 Boost with H5N1 clade 1 with MF59 Days Months

Fluad Pediatric V70P5 Pediatric Fluad® Efficacy Study (n=4707) Efficacy was robust, observed early, and persisted 1.0 0.8vs. non-influenza control 0.6 Vaccine efficacy 0.4 Vaccine also showed satisfactory safety profile: 0.2 • Increased local reactogenicity • No increase in serious adverse 0.0 experiences vs. control – 0.2 Fluad – 0.4 TIV – 0.6 0 20 40 60 80 100 120 140 160 180 200 220 Days post-second doseVesikari T, et al. NEJM. In press.

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

Structural Vaccinology 3 antigens in one

Structural Vaccinologyengineering a stable F protein for RSV

During the last 30 years, several new technologies made possible vaccines that were previously impossible Self amplifying RNA (SAM) Andy Geal & Chistian Mandl (PNAS)

Viral vectors: Alphavirus replicon particles  A Safe Vector: • Single round infection means no viral spread • RNA genome won’t integrate into the native genome  Good Immune Response 5 nsProteins JR Antigen 3 Nucleus • Functions as an Cytoplasmic immunostimulant amplification via dsRNA • Induces humoral and cellular immune response Subgenomic mRNA Antigen

Non-viral delivery with Lipid nanoparticles (LNPs)Encapsulation technology based on scaled-down industrial process Component Function Neutral Lipid Particle base Cationic Lipid RNA Loading Cholesterol Particle stabilization D=141 nm PEG - Lipid Particle stabilization Charge shielding Extended circulation Self-replicating Express antigen of RNA interest

Delivery systems protect RNA from RNases 1 2 3 4 5 Self-amplifying RNA 9 kb RNA protected from Rnase degradation (1) RNA ladder (2) Self-amplifying RNA (3) Self-amplifying RNA after exposure to RNase A (4) Phenol-chloroform extraction of self-amplifying RNA from an LNP (5) Phenol-chloroform extraction of self-amplifying RNA from an LNP after exposure to RNase A (5)

Potency of RSV SAM™ vaccine vaccinate (i.m.) vaccinate (i.m.)comparable to viral delivery technology Day: 0 21 * 35 49RSV F-specific IgG titers Comparative mouse immunogenicity studies of a LNP/RNA vaccine candidate encoding RSV F. Groups of 8 mice (except LNP/DNA, with 4 mice per group) were vaccinated on days 0 and 21, and sera were collected on day 35. F- specific IgG titers were determined by ELISA. Data are from individual mice are depicted as dots, and the geometric mean titers (GMT) of either 4 or 8 mice per group are depicted as solid lines. The dotted line indicates the limit of titer quantification (25). To calculate GMTs, titers < 25 were assigned a value of 5. ns – not significant.

vaccinate vaccinateSeroconversion after a single dose (i.m.) (i.m.)of RSV SAM™ vaccine Day: 0 * 14 21 * 35 49 (a) RSV F-specific IgG titers 2wp1 (b) RSV F-specific IgG titers 2wp2 * * Mouse immunogenicity studies of a LNP/RNA candidate vaccine encoding RSV F. Groups of 8 mice were vaccinated on days 0 and 21, and serum was collected on days 14 and 35. F-specific IgG titers were determined by ELISA for (a) 2wp1 and (b) 2wp2. Dots depict measurements from individual mice and solid bars depict the geometric mean titers of 8 mice per group. The dotted lines indicate the limits of quantification (25). For determination of GMT, a titer < 25 was assigned a value of 5. ns – not significant.

RSV SAM™ vaccine protects vaccinate (i.m.) vaccinate RSV challenge (i.m.) (i.n.)cotton rats from viral challenge * Day: 0 21 35 49 54 (a) Neut titers 2wp2 (b) IgG titers 2wp2 (c) Lung viral load * * p<0.05 p<0.05 60% RSV neutralization titer 10 5 ns 10 6 ns 10 7 RSV F-specific IgG titer 10 4 p<0.05 10 5 p<0.05 10 6 RSV pfu/g lung 10 4 10 5 10 3 10 3 10 4 2 10 10 2 10 3 10 1 10 1 10 2 10 0 10 0 10 1 A P/ A ne F/ P um P/ A ne A um F/ P ne F/ P P/ A A um N LN R N VR LN RN N VR VR LN RN N no no R al no al R R al Cotton rat data demonstrating potency and efficacy of a RNA vaccines encoding the surface fusion (F) glycoprotein of RSV (RSV F). Groups of 8 rats were vaccinated i.m. on days 0 and 21 with naked RNA (1 μg), LNP/RNA (1 μg), VRP (5 x 106 IU ), alum- formulated RSV F protein (10 μg), or were not vaccinated. All animals were challenged intranasally with 1 x 105 pfu RSV on day 49. (a) Serum RSV neutralization titers and (b) serum F-specific IgG titers 2 weeks after the second vaccination (day 35). (c) Lung viral load 5 days after the RSV challenge (day 54). Dotted lines indicate assay limits of detection.

vaccinate vaccinateHIV SAM™ vaccine induces potent (i.m.) (i.m.)CD8+ T cell responses Day: 0 14 21 * 35 49 (a) CD4+ T cell responses 2wp2 (b) CD8+ T cell responses 2wp2 * * Mouse immunogenicity study of a LNP/RNA vaccine encoding the HIV gp140 surface glycoprotein (SF162.o-gp140). Mice were immunized with 1µg RNA or 15 µg DNA on days 0 and 21. On day 35, pooled splenocytes were stimulated with Env-derived antigenic peptides, stained for intra-cellular cytokines, and subjected to flow cytometry. Graphs show the Env-specific (%) frequencies of CD4+ (a) or CD8+ (b) T-cells with error bars denoting 95% confidence limits. ns – not significant.

Producing RNA Does not require cell culture, complex purification, or novel equipment This is a platform technology Each vaccines requires a unique DNA template 4000 ml The Production process and other raw materials are generic RNA production compared to protein subunit RNA (100 µg human dose, 90% yield)  4 ml (5 mg/ml RNA) = 180 doses 4 ml  40 ml (5 mg/ml RNA) = 1,800 doses

During the last 30 years, several new technologies made possible vaccines that were previously impossible ADITEC, an EU funded program has as a mission to develop the knowledge and next generation technologies needed for the vaccines of the future

Vaccine knowledge and technologies38

During the last 30 years, several new technologies made possible vaccines that were previously impossible Vaccines Against Poverty

Vaccines against poverty A major challenge for developing countries in the 21st century Infectious diseases, in addition to causing morbidity and mortality, are a major contributor to poverty  In developing countries “they extract a huge toll from the income of each family and throw them into a downward spiral of poverty” (Leslie Roberts, Science 2008) Vaccination can control many of the infectious diseases

An Institute to address the gaps in vaccine developmentIn 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  Legal entity started in Feb 2007  Allan Saul hired as CEO Sept 2007  Inauguration Feb 22, 2008

Mission Reduce infant mortality and improve health and living conditions in low-income countries, by accelerating innovation and Redu introduction of life-saving vaccines able tooduction of life-saving vaccines able to eliminate neglected infe eliminate neglected infectious diseases and reduce poverty

Innovations in Vaccinology

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