Developing Pneumococcal, Meningococcal and Hib

Vaccines

George Siber MDCSO, ClearPath Vaccines

Adjunct Professor, Johns Hopkins UniversityBloomberg School of Public Health

Sabin Gold Medal Ceremony2016

Inspiration To Be Practical

“It’s good to learn the theory, but not enough. Make sure you do something useful with it.”

…so Building Became a PassionFor My Sister and Me

Inspiration to Study Medicine

Wilder Penfield 1891-1976 Canadian neurosurgeon Mapped regions of brain Founded the Montreal Neurological Institute

“The Torch” by Wilder Penfield

He beamed when I showed him my paperback copy of The Torch. “I had such fun writing it.” he said. “It’s the right way, really, the novelist approach. When you write imaginatively, you know what’s right. The historian can’t do that when he says such and such happened.”

Alan Blum, A Bedside Conversation with Wilder Penfield CMAJ 2011

Inspiration to Work on Vaccines

John F Enders - 1897-1985 Nobel Prize in Medicine - 1954Shared with Tom Weller and

Tony Robbins

First grew viruses in tissue cultureEnabled development of polio

and many other viral vaccines

Inspiration to Work on Hib, Pneumococcal and Meningococcal Vaccines

Porter Anderson

David Smith

John Robbins

Rachel Schneerson

Albert Lasker 1996 Clinical Medical Research Award

for the Hib Conjugate Vaccine

Heroes and Mentors

Maurice Hilleman Bob Austrian Stanley Plotkin

Rino Rappuoli

Roger Glass Al Kapikian and Bob Chanock

Marc LaForce

Why Hib, Pneumococcus and Meningococcus?

Three most serious bacterial infections of mankind: H. influenzae b (Hib): most common cause of bacterial

meningitis. Pneumococcus: single most common cause of serious

bacterial infection of children and adults, including pneumonia, sepsis and meningitis.

Meningococcus: though rare, causes overwhelming sepsis and meningitis. Can be fatal within 24 hours.

Otitis media

Pneumonia

Bacteremia

Meningitis

Dis

ease

sev

erity

Number of cases/yr. in US

( > 1000 X)

( ~X 100)

( ~X 10)

Prevalence

Invasive

Noninvasive

Pneumococcal Disease Burden in US Children

Adapted from: American Academy of Pediatrics. Pediatrics. 2000;106:367-376 & MMWR. 1997;46:1-24

13,000

71,000

5 Million

700

Global Burden of Pneumococcal Disease in Children

Hib, Pneumococcus and Meningococcus Are Surrounded By a Complex Sugar Coating

The surface capsule defines the serotype.

The capsule is a major virulence factor.

Antibody to capsular polysaccharide is protective.

Bar = 100 nm

Early Work

Important to make the Dx quickly to prevent serious complications: developed a simple Dx test that give results in minutes.

But early Dx is not good enough: Children with cancer or lacking their spleen often die within 24h despite optimal antibiotic Rx.

Pediatrics. 1982;69:466-71Am J Dis Child. 1980;134:668-72

If Treatment was Not Good Enough, We Had to Prevent the Infections

Who was at highest risk? Children who had both radiation and chemo had the lowest antibodies to polysaccharide antigens.

But, immunizing them with investigational Ps vaccine did not work. The more treatment they had, the lower the antibody and the higher the risk.

Found that the low polysaccharide antibody correlated with low levels of a subclass of antibodies called IgG2.

NEJM. 1977;297:245-8NEJM. 1978;299:442-8NEJM. 1980;303:178-82

..If They Can’t Respond to Vaccine, Then We’ll Find Somebody Who Can and Make Antibodies for Them

Immunized blood and plasma donors with the available Ps vaccines to Hib, pneumococcus and meningococcus.

Donna Ambrosino

Enlisted Massachusetts Biologic Labs (MBL) for Help Had capability to purify

human Ab by cold alcohol fractionation (Bacterial Polysaccharide Immune Globulin or BPIG)

Infect Immun. 1984;45(1):248-54

George Grady

Massachusetts Biologic Labs (MBL)

Founded in 1894 by Massachusetts DPH to make diphtheria antitoxin

Theobald Smith, the “father of American Microbiology” and discoverer of Salmonella was the first Director

First of 6 state-run biologic labs in the US

Evaluation of BPIG

Showed BPIG worked in animals

Showed good antibody levels in high-risk children

Infect Immun. 1983;39:709-14J Infect Dis. 1986;153(1):1-7

Claudette Thompson

How Do We Show That BPIG Works?

Need hundreds of children at high risk. Difficult to do with cancer patients or patients post-splenectomy…

Saved by a call from Mathu Santosham

Mathu Santosham

Richard Moxon

…moi talking to Mathu

BPIG Study Group – Apache Reservation

Left to Right: Ray Reid, George Siber, Mathu Santosham,Claudette Thompson, Janne Croll and Mark Wolff

Front Row: Richard Moxon, Donna Ambrosino

Pamela McInnesDavid Klein

Many Wonderful Site Visits Later We Got Great Results…

Efficacy of BPIG vs. Hib and Pneumococcal Disease

NEJM. 1987;317(15):923-9

BPIG was Introduced into Alaska Native Population

Singleton et al. Decline of Haemophilus influenzae type b disease in a region of high risk: impact of passive and active immunization. Pediatr Infect Dis J. 1994;13:362-7

Jim Berner

Ros Singleton

BPIG: Opportunity for Scientific Discoveries

Genetic factors affecting ability to make Ab to polysaccharide antigens in adult donors.

Found impaired Ab responses of Apache children to Hib Ps vaccine.

Development of standardized antibody assays and antibody standards still used in vaccine evaluations today.

Defined protective antibody levels to Hib and pneumococcus that were associated with protection: used as basis to license future vaccines.

Hib Antibody Levels in BPIG Recipients

NEJM. 1987;317(15):923-9

BPIG: Opportunity to Lead MBL 1982-1996

FDA licensed, public sector vaccine facility

State budget was ~ $1M/year Survival depended on developing

new products

MBL Staff - circa 1984

Products Developed at MBL 1982-1996

1. Varicella Zoster Immune Globulin (VZIG)2. BPIG3. CMVIG-IV (Cytogam)4. RSVIG-IV (Respigam) Synagis (MedImmune)5. Pertussis toxoid vaccine6. Pertussis Immune Globulin (PIG) 7. Botulism IG for infant botulism (Baby-BIG)8. Hib-TT conjugate (as component of Quinvaxem)

RSV Immune Globulin (Respigam)

Collaboration with USUHS and MedImmune (1989) Trial funded by NIAID Efficacy vs severe RSV demonstrated (Groothuis et al.) Market approval (1996) – follow-on product: Synagis

Wayne Hockmeier, George Siber, Frank Top and Val Hemming Jeanne Leszczynski

Jim McIver

Donna Ambrosino – MBL CEO 1998-2011

Established new facilities with MAb development and manufacturing capacity.

Developed MAbs to Rabies, C. difficile toxins and Hepatitis C.

George Siber, Donna Ambrosinoand Jeanne LeszczynskiDonna Ambrosino

Mass Biologics Manufacturing Building Dedication – May 12, 2006

Licensed Conjugate Vaccines

• Hib conjugate (US - 1990)• Meningococcal C (UK – 1999)• Pneumococcal 7-valent (PCV7: US – 2000)• [Meningococcal 4-valent (US - 2005)]• [Pneumococcal 10-valent (EU – 2009)]• Pneumococcal 13-valent (PCV13: US – 2010)

Polysaccharide Vaccines Stimulate Only B Cells

Polysaccharidespecific antibody

**

B

• Do not recruit T cell help• No immunologic memory, no boosting• Do not induce protective Ab response in children

Conjugate Vaccines Were Developed to Solve Shortcomings of PS Vaccines

PS are covalently linked to proteins to convert a T-independent antigen into a T-dependent antigen:

Protein

+

Polysaccharide Conjugate

• Conjugates induce protective antibodies in infants• Boost the antibody response

Decline of Haemophilus influenzae Meningitis in U.S. Children UnderFive Years Following Introduction of Haemophilus B Conjugate Vaccines

All Laboratory Confirmed Cases of Meningococcal Disease (by quarter) England & Wales.

0

100

200

300

400

500

600

700

800

1997 1998 1999 2000 2001 2002

no o

f cas

es

Serogroup CSerogroup B

Immunisation with MCC began

Courtesy of Dr Ray Borrow, PHLS

Impact of Meningococcal C Conjugate Vaccine in the UK

David Salisbury

Invasive Pneumococcal Disease Serotypes in North American Young Children

0

5

10

15

20

25

30

14 6B 19F18C23F 4 9V 19A 6A 9N 18B18F 7F 3 1 22F15C12F11A33F10A 38 13Serotype

Tota

l inv

asiv

e di

seas

e (%

)

0102030405060708090100

Cum

ulat

ive

(%)

Vaccine types

Cross-reactivetypes

Noncross-reactive types

Hausdorff WP et al. Clin Infect Dis. 2000;30:100-121.Hausdorff WP et al. Unpublished data, 1999.

Conjugates are mixed to formulate vaccineConjugates are mixed to formulate vaccine

Prevnar

Large scale fermentation and purification of saccharideLarge scale fermentation and purification of saccharide

4 6B6B 9V9V 14 18C18C 19F19F 23F23F

QC

MANUFACTURING PROCESS FOR PREVENAR™MANUFACTURING PROCESS FOR PREVENAR™

QC

Each type of saccharide is separately activated and conjugated to CRM protein carrier

Each type of saccharide is separately activated and conjugated to CRM protein carrier

QC

Kaiser Permanente Vaccine Trial: Invasive Pneumococcal Disease Efficacy (Vaccine Serotypes)

ControlSubjects PCV7 (Mening C) Efficacy (95%CI)(n=38,000)Per protocol 1 39 97.4% (84.8, 99.9)

Intent-to-treat 3* 49 93.9% (81.0, 98.8)

* 1 fully vaccinated after 4 doses1 partially vaccinated with 1 dose1 immuno-compromised

Black et al. Pediatr Infect Dis J. 2000;19:187-95

Steve Black Henry Shinefield

2000 Invasive Disease

2001 Otitis Media

2003 Invasive Disease

2004 Invasive Disease/Pneumonia

2005 Invasive Disease/Pneumonia/Death

Pneumococcal Conjugate Vaccine Efficacy Trials in Infants

97.4%

57%

83% 20%(CXR +ve)

76.8%

Kaiser Permanente, CA

Finland

Navajo Indians

Soweto, S. Afr.

The Gambia77%/37%/16%

Courtesy of David Goldblatt

#1

#2

#3

#4

#5

PCV7 intro-

duction

Rates of IPD Among Children Aged

Rates of IPD Caused by PCV7 Serotypes Among Adults >18 Years Old - ABCs 1998-2009

2009 vs. baseline65+: -97% (-96,-98)

50-64: -92% (-89,-94)

18-49: -96% (-94,-97)

PCV7 Intro-

duction

What is Herd Immunity? Partially Vaccinated Population Prevents the Spread of Infection

x

x x

Courtesy of Matt Moore, CDC

Vaccine-Type Invasive Pneumococcal Disease Prevented by Direct and Indirect Effects of PCV7 - ABCs 2003

9,140

20,460

0

5,000

10,000

15,000

20,000

25,000

Direct effects Indirect effects

Estim

ated

no.

cas

es p

reve

nted

CDC. MMWR Sep 16, 2005

Invasive Pneumococcal Disease Burden (US)

0

200

400

600

800

1000

1200

1400

1600

1800

2000

80Age Group

Estim

ated

# D

eath

s

0

20

40

60

80

100

120

140

160

180

80Age Group (Years)

Cas

es p

er 1

00,0

00

Robinson et al. JAMA 2001;285:1729

Cases

Deaths

Rates of IPD Caused by Serotype 19A Among Adults >18 Years Old - ABCs 1998-2009

Age, years

Percent change (95% CI)

Rate difference

65+ +157% (+81,+264) 3.5

50-64 +372% (+184,+684) 2.7

18-49 +251% (+138,+418) 0.98

Pneumococcal Conjugate Vaccines

PCV7 Introduced in United

States in Feb 2000Contains serotypes:

4, 6B, 9V, 14, 18C, 19F, 23F

PCV13 Introduced in United

States in March, 2010Contains PCV7 serotypes

+ 1, 3, 5, 6A, 7F, 19A

Carrier protein

Carrier protein

Cumulative PCV6-type IPD Cases Among Children Aged

PCV13 N = 110; 23vPS N = 107* statistically significant

0

2

4

6

8

10

12

14

16

18

4 6B 9V 14 18C 19F 23F

Prevnar

23vPS

*

*

* *

**

GMC Antibody for PCV13 superior to 23vPS

Better Immunogenicity of PCV in Adults

Efficacy of PCV13 vs Community Acquired Pneumonia (CAP) in Adults (CAPITA trial1)

PCV13, n = 42,240; Placebo, n = 42,256 VT = vaccine type

0102030405060708080

100

Vacc

ine

effic

acy

(%)

Prevention of VT pneumococcal

CAP

46%p < 0.001

45%p = 0.007

75%p < 0.001

Prevention of VT nonbacteremic pneumococcal

CAP Prevention of VT IPD

Reduction in Pneumococcal Disease with PCV13

Bonten MJM, et al. NEJM. 2015;372:1114–25.

Estimated Impact of PCV7 and PCV13 in the US

Pneumonia Hospitalizations (Griffin 2013) Prevented 168,000 cases/year (after PCV7)

Pneumococcal disease: 2000-2012 after PCV7 and 13 (Moore 2015) Prevented 400,000 episodes of invasive

pneumococcal disease (>50% in adults) Prevented ~30,000 deaths (~90% in adults)

Global Burden of Pneumococcal Disease in Children

Estimated Impact of Underutilized Vaccines Globally: 2011-2020

Global Vaccine Action Planhttp://www.who.int/immunization/global_vaccine_action_plan/GVAP_doc_2011_2020/en/

Haemophilus influenzae Type B

Pneumococcus

Meningococcal A meningitis

Rotavirus

1.4 – 1.7M

1.6 – 1.8M

0.03M

0.8 – 0.9M

Credit Goes to 100’s of People Who Contributed to Developing the PCV Vaccine

Seed Funding Research & Development Antibody assays and diagnostics Clinical trials Statistics and correlates of protection Regulatory and policy Measure the vaccine effect Implementation/global uptake

Seed Funding - NIAID

John LaMontagneBill Jordan Carole Heilman Pamela McInnes

Prevenar R&D Team - Wyeth

Lung Hsieh Puvy Bob Corder Arum

Jim Cowell Brad Kosiba Bruce GreenMaya Koster

Antibody Assays are Key!

Helena Kaythy

Dace Madore Sally Quatert David Goldblatt

Moon Nahm George Carlone

Dan Sikkema

Tim McDermott

Siber et al. Vaccine. 2007 (19) 3816

0.01 0.15 0.35 1 2 4 8 16 32 64

7vPnC withMnCC without

% S

ubje

cts

0

10

20

30

40

50

60

70

80

90

100

Antibody Concentration

[C]prot without 22F = 0.35µg/ml [C]prot with 22F = 0.32 µg/ml

7vPnC without 22F 7vPnC with 22F MnCC without 22FMnCC with 22F

Estimating the Protective Level of Antibodies to Pneumococci (0.35 µg/ml)

Bob Kohberger

Ih Chang

Prevenar: National Medal of Technology – 2005

Other Awards• ACS Heroes of Chemistry 2003• Prix Galien 2003• Discoverer’s Award 2005• Prix Galien (13-V) 2011

Clinical Development

Keith KlugmanJuhani Eskola Mathu Santosham Kate O’Brien

Bill Gruber Jill Hackell Steve Lockhart Beate Thoma

Clinical Study Collaborators

Regulatory Approvals and Recommendations

Carolyn Hardegree KKaren MidthunNorman Baylor Karen Goldenthal

Peter Paradiso Bernard Fritzell Jack Love Doug Pratt

Measuring the Vaccine Effect

Claire Broome Anne Schuchat Liz Miller Jay Butler

Cindy Whitney Matt Moore Kate O’Brien

Global Implementation

Is the Pneumococcal Problem Solved?No. We Need to Work on Even Better Vaccines!

Genocea Team

Affinivax Team

• Broader coverage• Simpler to make• Lower cost

Finally… a Special Thanks to Two of My Strongest Supporters!

Developing Pneumococcal, Meningococcal and Hib

Vaccines

George Siber MDCSO, ClearPath Vaccines

Adjunct Professor, Johns Hopkins UniversityBloomberg School of Public Health

Sabin Gold Medal Ceremony2016