Bite of Science, Orlando Brian Schanen, Ph.D.

Photo

cre

dits:

©

CREATING

VACCINES,

PROTECTING

LIFE

Objectives for Today

• Introduce Sanofi Pasteur

• Brief Career History

• My Division’s Research

• Systems Biology

• Connecting Careers to the Classroom

• STEM in the “real-world”

• Coursework of interest

• Key to success in STEM fields

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About Sanofi Pasteur

Sanofi

A diversified global

healthcare leader, focused

on patients’ needs

Sanofi Pasteur

World’s largest human

vaccines company, a

division of Sanofi

Headquarters

Lyon, France

Headquarters

Paris, France

Employees

~15,000

Invests in R&D

More than €1 million

Invested every day

2016 net sales

€36,529 million

+3.4% versus 2015

2016 net sales

€4,577 million

+8.8% versus 2015

Employees

~115,000

In 100 countries

Global R&D

44 NME and vaccine

candidate in development

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Sanofi Pasteur, A World Leader In Vaccines

15,000

EMPLOYEES

COMMITTED

TO

PUBLIC

HEALTH

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Toronto (Canada)

Connaught Laboratories

is founded

Lyon

Institut Mérieux is founded

Institut Mérieux buys Institut

Pasteur Production.

Pasteur Vaccins is founded

Our Remarkable Heritage

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Sanofi Pasteur acquires VaxDesign, a U.S. biotechnology company 2010

Sanofi Pasteur acquires Shantha Biotechnics 2009

Sanofi Pasteur Holding acquires Acambis plc 2008

Sanofi Pasteur: new name after Sanofi acquired Aventis 2004

Aventis Pasteur : nouvelle dénomination après la fusion entre Rhône-Poulenc et Hoechst pour former Aventis 1999

Pasteur Merieux Connaught : global name after Rhone Poulenc acquired Pasteur Merieux Serums & Vaccins in 1994 1997

Pasteur Mérieux Sérums & Vaccins 1990

Institut Merieux acquires Connaught Laboratories 1989

1985

Val de Reuil

Institut Pasteur Production is founded 1973

Connaught Laboratories acquires Swiftwater Salk

Institute Laboratories 1978

1914

Swiftwater (US)

Pocono Biological Laboratories is founded 1897 1897

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8

Leaders In Global Vaccine Production

• Unparalleled production capacity to meet the increasing global demand for vaccines

• Our priority is to produce vaccines that meet the highest standards of quality and reach as many people as possible

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Val de Reuil

Marcy-l’Etoile

Neuville Toronto

Shenzhen

Swiftwater (PA)

Canton (MA)

Rockville (MD)

Pilar

Chachoengsao Hyderabad

Ocoyoacac

12 sites

More than

50% of our

headcount dedicated

to industrial operations

More than 1 billion vaccine doses

produced each year

9

Research And Development

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● In research and development, our priorities are: new vaccines,

improvements to existing vaccines, new combination vaccines

(particularly for children), new vaccine technologies

● We anticipate and propose innovative solutions to improve access

Toronto

Marcy-l’Etoile

Swiftwater (PA)

Cambridge (MA)

Orlando (FL)

Hyderabad

Beijing

7 sites

15% of total headcount

More than

18,000 man-hours

invested daily

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Vaccination Explained Simply

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• Vaccination is the act of immunizing an individual against an infectious disease, by administering a vaccine

• Vaccines stimulate the immune system of an individual to help them avoid getting an infection or disease

Vaccination is a Global Priority

Vaccines can easily become the “ forgotten hero ” in the health-care field.

• Vaccination has significantly improved global health and decreased mortality from vaccine preventable diseases, such as smallpox, polio, pertussis, and diphtheria.

• According to the World Health Organization, as many as 3 million people die of vaccine-preventable diseases in a single year.

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Vaccination: Improving Global Public Health

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1 WHO European Region – Seven key reasons why immunization must remain a priority […]

2 Johns Hopkins Bloomberg School of Public Health; 2016

3. WHO - Immunization highlights: 2013

3 million lives(1) saved worldwide

each year

IMMUNIZATION

SAVES LIFE

REQUIRES

PUBLIC HEALTH

INVESTMENT

CHALLENGES

REMAINS

Vaccinations save $44 for

every $1spent on vaccines(2)

1 in 5 children are still missing

out: in 2013, an estimated 21.8 million infants did not receive life saving vaccines(3)

Objectives for Today

• Introduce Sanofi Pasteur

• Brief Career History

• My Division’s Research

• Systems Biology

• Connecting Careers to the Classroom

• STEM in the “real-world”

• Coursework of interest

• Key to success in STEM fields

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What Inspired Me?

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Educational and Career Path

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Music Major, Instrumental Micro/Molecular Biology, B.S.

Biomedical Sciences, M.S.

Ph.D., Immunology and Nanotechnology

Undergrad Lab Experience

First industry position, VaxDesign

Industry Career Ladder

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No Two Days are the Same

• Interfacing with my team (15%)

• Progress updates, troubleshooting and next steps

• Planning experiments

• Meeting with senior leadership (20%)

• Updating on project key milestone achievements

• Word, Powerpoint…

• Business Development

• Project Management (50%)

• Managing HC across projects

• Budgeting experimental resources

• Administrative duties

• Personnel management (HR)

• Project Reporting

• Grant writing/collaborations

19

Associate Director

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• Innovation

• Staying current with literature

• Adopting/developing state-of-the-art technologies

• Scientific writing

• Preparing manuscripts

Immunologist, Systems Biologist and Bioinformatician

Objectives for Today

• Introduce Sanofi Pasteur

• Brief Career History

• My Division’s Research

• Systems Biology

• Connecting Careers to the Classroom

• STEM in the “real-world”

• Coursework of interest

• Key to success in STEM fields

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A Portfolio Of High Quality Vaccines

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Bacterial diseases Viral diseases

Smallpox Eradicated disease

This vaccine is produced in response to the threat of bioterrorism.

Dengue

Hepatitis A

Hepatitis B

Influenza

Japanese encephalitis

Measles

Mumps

Poliomyelitis

Rabies

Rubella

Yellow fever

Cholera

Diphtheria

Haemophilus influenzae type b infections

Meningococcal meningitis

Pertussis

Pneumococcal infections

Tetanus

Tuberculosis

Typhoid fever

The Vaccine Development Cycle

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Average development

time for a vaccine: 12 years of a vaccine’s production time

dedicated to quality control. 70%

Overall cost to develop

a vaccine investment: More than half a billion US dollars

R&D Portfolio

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Herpes Simplex Virus

Type 2

HSV-2 vaccine

Zika

Inactivated Zika vaccine

Respiratory syncytial

virus

Infants

PHASE I PHASE II

Rabies VRVg

Purified vero rabies vaccine

Tuberculosis

Recombinant subunit

vaccine

Fluzone® QIV HD

Quadrivalent inactivated

influenza vaccine – high

dose

Adacel+

Tdap booster

Shan 6

DTP-HepB-Polio-Hib

Pediatric hexavalent

vaccine

HIV

Viral vector prime & rgp 120

boost vaccine

Clostridium difficile

Toxoid vaccine

VaxiGrip® QIV IM

Quadrivalent inactivated

influenza vaccine (6-

35months)

Pediatric pentavalent

vaccine

DTP-Polio-Hib Japan

PHASE III

Men Quad TT

2nd generation

meningococcal ACYW

conjugate vaccine

Dengvaxia® (1)

Mid-to-severe dengue fever

vaccine

PR5i

DTP-HepB-Polio-Hib

Pediatric hexavalent

vaccine U.S.

VaxiGrip® QIV IM (2)

Quadrivalent inactivated

influenza vaccine (3years+)

REGISTRATION

As of February 8, 2017 (1): approved in 14 countries

(2): approved in 27 countries

• Humans and laboratory animals display numerous discrepancies in both innate and adaptive immunity:

• T-cell subsets, cytokine receptors

• Costimulatory and TLR molecule expression and function

• Th1/Th2 differentiation

• The MIMIC system can be used as an additional tool to conduct pre-clinical research

Filling the Gap Between Animal Studies and the Clinic

MIMIC Overview 25

VaxDesign Started with Engineers, not Biologist…

NEED: BIOMIMICRY

OF THE HUMAN

IMMUNE SYSTEM

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MORE THAN

ENGINEERING

HUMAN IMMUNITY

Can we simplify our design?

| 27

http://mdxresearchmethods.wordpress.com/2012/02/29/occams-razor/

VaxDesign: Modeling Human Immunology in vitro

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MIMIC System and Star Trek Parallelisms

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• Immunology: • The untapped human frontier

• Our mission • To explore strange new diseases • To boldly go where no one has looked before

Modeling human physiology to evaluate innate immunity

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Schanen, Brian C., et al. Journal of immunological methods 335.1 (2008): 53-64.

• Physiological Relevance

• Fully autologous

• No exogenous cytokines

• DC subset heterogeneity

• Functional Outcomes

• DC Phenotyping

• Inflammatory profiling

• Viable APCs for priming LTE

Engineering adaptive immune responses

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Fundamental design observations:

• The right cell types: CD4 T cells, B cells, DCs • At the right times • In the right order • In an automatable, scalable system

Modeling B and T cell Responses

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Systems Approaches

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Bex-0.5 Bex-5 Bp82-0.5 Bp82-5 DTaP No Ag YF Vax

YF Vax

No Ag

DTaP

Bp82-5

Bp82-0.5

Bex-5

Bex-0.5

Bioengineering

Identify differentially expressed genes

DTaP No Ag YF Vax Bp82-0.5 Bp82-5 Bex-0.5 Bex-5

STAT1

IRF9

CASP1

CXCL2

CD83

IL12B

CCL2

IL23A

CCL5

IFNB1

BCL2L14

APOBEC3B

NFKBIZ

NFKB1

NFKBIA

CXCL3

IL1B

LAMP3

CXCL1

CCL4

IL6

CD38

CCL8

TNFAIP6

APOBEC3F /// APOBEC3G

OASL

ISG15

PNPT1

OAS3

IFITM1 /// IFITM2

IFITM1

OAS1

TRIM22

ISG20

IFI27

USP18

EIF2AK2

IFIT2

IFIT1

IL15

GBP1

CARD16 /// CASP1

GBP4

IRF9 /// RNF31

GBP5

GBP5

IRF1

CXCL10

CCL13

CXCL9

APOBEC3A /// APOBEC3A_B

TNFSF10

MX1

MX2

CD69

APOBEC3G

CXCL11

DTaP No Ag YF Vax Bp82-0.5 Bp82-5 Bex-0.5 Bex-5

STAT1

IRF9

CASP1

CXCL2

CD83

IL12B

CCL2

IL23A

CCL5

IFNB1

BCL2L14

APOBEC3B

NFKBIZ

NFKB1

NFKBIA

CXCL3

IL1B

LAMP3

CXCL1

CCL4

IL6

CD38

CCL8

TNFAIP6

APOBEC3F /// APOBEC3G

OASL

ISG15

PNPT1

OAS3

IFITM1 /// IFITM2

IFITM1

OAS1

TRIM22

ISG20

IFI27

USP18

EIF2AK2

IFIT2

IFIT1

IL15

GBP1

CARD16 /// CASP1

GBP4

IRF9 /// RNF31

GBP5

GBP5

IRF1

CXCL10

CCL13

CXCL9

APOBEC3A /// APOBEC3A_B

TNFSF10

MX1

MX2

CD69

APOBEC3G

CXCL11

Expression patterns, correlations and network analysis

AIDING VACCINE DEVELOPMENT BY

EXPOSING MECHANISM OF ACTION

Bioinformatics Immunology

Using the MIMIC System to Evaluate Vaccine Candidates

• Bacterial OMV vaccine candidates were evaluated for potency and immunogenicity • Analysis assisted in down-selection of the vaccine candidates

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Co

un

t C

D8

0+

5 0 5 .5 5 0 5 .50

5 0 0

1 0 0 0

1 5 0 0

2 0 0 0

B P 8 2 (n g /m L ) B e x s e ro (n g /m L )

LP

S+

R8

48

No

Ag

Co

un

t C

D8

6+

5 0 5 .5 5 0 5 .50

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0

B P 8 2 (n g /m L ) B e x s e ro (n g /m L )

LP

S+

R8

48

No

Ag

CD80 CD86 IL-12p40

Co

nc

en

tra

tio

n (

pg

/mL

)

5 0 5 .5 5 0 5 .50

5 0 0

1 0 0 0

1 5 0 0

B P 8 2 (n g /m L ) B e x s e ro (n g /m L )

LP

S+

R8

48

No

Ag

n = 20

Ag 1 Ag 2 Ag 1 Ag 2 Ag 1 Ag 2

Dr. Morici

Differential Gene Expression Pattern Between Candidates

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215

384 470

369

2105

1736

2119

1985

Ag 2 0.5 ng Ag 2 5.0 ng

Ag1 0.5 ng Ag1 5.0 ng

Dif

fere

nti

ally

exp

ress

ed g

enes

p-value

Ag 1

Ag 1

Ag 2

Ag 2

Immunogenicity Profile Similar to a Licensed Vaccine at a Log Lower Dose

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Inflam

maso

me R

elated G

enes

Ag1 5.0

Ag1 0.5

Ag2 0.5

Ag2 5.0

Ag 1-5ng

Y = -0.0907 + 0.5637 * X N=99Correlation=0.8026PValue=0.0000e+000

-3 -2 -1 0 1 2 3 4 5 6

Treatment => Bp82-5 vs No Ag.Estimate

-1

0

1

2

3

4

Tre

atm

en

t =

> B

ex-5

vs N

o A

g.E

stim

ate R2=0.801

Y = 0.0114 + 0.6464 * X N=99Correlation=0.8584PValue=0.0000e+000

-2 -1 0 1 2 3 4 5 6

Treatment => Bp82-0.5 vs No Ag.Estimate

-1

0

1

2

3

4

Tre

atm

en

t =

> B

ex-5

vs N

o A

g.E

stim

ate R2=0.858

Ag 1-0.5ng

R2=0.650

Enhanced Innate Immune Activation

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Inn

ate

Imm

un

e R

elat

ed G

enes

Granulocyte

Adhesion and

Diapedesis

Differential regulation

of cytokine production

Communication

between innate and

adaptive cells

Role of pattern

recognition

receptors

0.0 2.5 10.0 5.0 7.5 12.5

-log(p-value)

Thre

sho

ld

Pathway Analysis

Ag1 5.0

Ag1 0.5

Ag2 0.5

Ag2 5.0

Differential Polyfunctional Th1 Responses

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No

An

t i ge

n

Bp

82

Bt

0 . 0

0 . 5

1 . 0

1 . 5

2 . 0

2 . 5

% C

D4

+C

D1

54

+IF

N

+

*p=0.0094

*p=0.0134

Targets

𝑛 = 16

No Antigen Ag 1 Ag 2

IFNγ

CD

15

4

Ag1 Ag2

Ag 1 OMV Generated Antigen-specific IgM And class-switched IgG Antibody Responses

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25% 42% 83%

B P 8 2

10

0 n

g E

26

4

10

ng

E2

64

1 n

g E

26

4

10

0 n

g B

P8

2

10

ng

BP

82

1 n

g B

P8

2

0

1

2

3

1 5

3 0

Ag-1-specific Abs

Stim

ula

tio

n In

dex

: O

MV

/ N

o A

g

10

0 n

g E

26

4

10

ng

E2

64

1 n

g E

26

4

10

0 n

g B

P8

2

10

ng

BP

82

1 n

g B

P8

2

0

1

2

3

1 0

25% 50% 83%

Stim

ula

tio

n In

dex

: O

MV

/ N

o A

g

IgG

IgM

B P 8 2

10

0 n

g E

26

4

10

ng

E2

64

1 n

g E

26

4

10

0 n

g B

P8

2

10

ng

BP

82

1 n

g B

P8

2

0

1

2

3

1 5

3 0

10

0 n

g E

26

4

10

ng

E2

64

1 n

g E

26

4

10

0 n

g B

P8

2

10

ng

BP

82

1 n

g B

P8

2

0

1

2

3

1 0

Ag1

Ag1

Ag1

IL-17 Activation, a Crucial Mechanism of Action

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Research & Development

41 BITE of SCIENCE

More than

€1 Million Invested every day in R&D

Almost

2000 R&D employees worldwide

14 Innovative vaccines in

clinical development

Nearly

100% Of Sanofi Pasteur’s exploratory

projects are partnered

Objectives for Today

• Company Background

• Brief personal history

• My Division’s Research

• Connecting Careers to the classroom

• STEM in the “real-world”

• Coursework of interest

• Key to success in STEM fields

BITE of SCIENCE 42

Real-World Application of STEM

• Science

• Accepting Failure and moving on…

• Experimental Method

• The manipulation of variables to test a hypothesis

• Critical Thinking

• Critical Listening

• Fostering an innovative spirit

• Broaden expertise across multiple disciplines

• PhD often narrows your focus, those with diverse backgrounds have an advantage

• Scientific writing

• Syntax - Sentence Structure and Types of Sentences – Grammar

• Strong analytical skills

• Expertise in the modeling and analysis of data.

• Data Presentation

• Literature reviews

• Know how to text mine

43 BITE of SCIENCE

http://www.bioedonline.org/lessons-and-

more/focus-on-stem/super-stem-sleuths1/

Real-World Application of STEM

• Computer programming savvy

• Advanced scientific data plotting software

• Prism, SAS/JMP

• Perl, Python and R

• Language of bioinformatics

• http://codehs.com/

• Engineering

• Robotics– automation is critical for survival

• Resourcefulness – repairing boards or problem solving electronic issues

• https://www.studentrobotics.org/

44

Technology

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Real-World Application of STEM

• Competency in Biostatistics

• Regression

• Bayesian Networks

• Multivariate Analysis

• Machine Learning

• SVM

• Neural Networks

45

Mathematics

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log Titer28 = α + λ ⋅ log Titer0 + βclin ⋅ Xclin + βg,c ⋅

c

Clustercgene g

+ γq ⋅ Studyqq

+ ϵ

𝜖 ~𝒩 0, 𝜎

2

CYD56 Transcriptomics | 46

Thank you!