Developing Pneumococcal, Meningococcal and Hib Vaccines

George Siber MD CSO, ClearPath Vaccines Adjunct Professor, Johns Hopkins University Bloomberg School of Public Health

Sabin Gold Medal Ceremony 2016 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 Passion For 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 - 1954 Shared with Tom Weller and Tony Robbins

 First grew viruses in tissue culture Enabled development of polio and many other viral vaccines Inspiration to Work on Hib, Pneumococcal and Meningococcal Vaccines

Albert Lasker 1996 Clinical Medical Research Award

Porter Anderson John Robbins

for the Hib Conjugate Vaccine

David Smith Rachel Schneerson Heroes and Mentors

Maurice Hilleman Bob Austrian Stanley Plotkin

Roger Glass Al Kapikian and Bob Chanock Rino Rappuoli 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. Pneumococcal Disease Burden in US Children

Invasive Number of cases/yr. in US 700

Meningitis Prevalence 13,000 ( ~X 10) Bacteremia 71,000 ( ~X 100)

Disease severity Pneumonia 5 Million ( > 1000 X) Noninvasive Otitis media

Adapted from: American Academy of Pediatrics. Pediatrics. 2000;106:367-376 & MMWR. 1997;46:1-24 Global Burden of Pneumococcal Disease in Children <5 Years (Deaths)

O’Brien Lancet 2009 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;69:466-71 Am 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;297:245-8 NEJM. 1978;299:442-8 NEJM. 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)

George Grady

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

Claudette Thompson

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

…moi talking to Mathu Mathu Santosham

Richard Moxon BPIG Study Group – Apache Reservation

David Klein Pamela McInnes

Left to Right: Ray Reid, George Siber, Mathu Santosham, Front Row: Claudette Thompson, Janne Croll and Mark Wolff Richard Moxon, Donna Ambrosino 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

Ros Singleton

Jim Berner

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 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. BPIG 3. CMVIG-IV (Cytogam) 4. RSVIG-IV (Respigam) Synagis (MedImmune) 5. Pertussis toxoid vaccine 6. 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, Jeanne Leszczynski Jim McIver Frank Top and Val Hemming 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 Ambrosino Donna Ambrosino and Jeanne Leszczynski 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

* *

Polysaccharide specific antibody B

• Do not recruit T cell help • No immunologic memory, no boosting • Do not induce protective Ab response in children <2 y • Repeat doses in adults may induce tolerance 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 Under Five Years Following Introduction of Haemophilus B Conjugate Vaccines Impact of Meningococcal C Conjugate Vaccine in the UK

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

800 Serogroup C Immunisation with MCC began David Salisbury Serogroup B 700

600

500

400 no of cases 300

200

100

0 1997 1998 1999 2000 2001 2002

Courtesy of Dr Ray Borrow, PHLS Invasive Pneumococcal Disease Serotypes in North American Young Children

30 100 Vaccine types 90 25 80 20 70 60 15 50

40 Cumulative (%) 10 30 Cross-reactive types 20 5 Noncross-reactive types Total invasive disease (%) invasive Total 10 0 0 14 6B 19F18C23F 4 9V 19A 6A 9N 18B18F 7F 3 1 22F15C12F11A33F10A 38 13 Serotype

Hausdorff WP et al. Clin Infect Dis. 2000;30:100-121. Hausdorff WP et al. Unpublished data, 1999. ™ MANUFACTURING PROCESS FOR PREVENAR

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

Large scale fermentation and purification of saccharide

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

QC Conjugates are mixed to formulate vaccine

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

Control Subjects 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 doses 1 partially vaccinated with 1 dose 1 immuno-compromised

Steve Black Henry Shinefield Black et al. Pediatr Infect Dis J. 2000;19:187-95 Pneumococcal Conjugate Vaccine Efficacy Trials in Infants

97.4% #1 2000 Invasive Disease Kaiser Permanente, CA #2 2001 Otitis Media 57% Finland #3 2003 Invasive Disease 76.8% Navajo Indians #4 83% 20% 2004 Invasive Disease/Pneumonia (CXR +ve) Soweto, S. Afr. #5 2005 Invasive Disease/Pneumonia/Death The Gambia 77%/37%/16%

Courtesy of David Goldblatt Rates of IPD Among Children Aged <5 years, 1998-2009 – USA, ABC Network

2009 vs. Average 1998-99

Percent change Rate Types (95% CI) difference All -76 (-79,-73) -75

PCV7 -100 (-100,-99) -81

19A +284 (+160,+466) +8

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

PCV7 2009 vs. baseline Intro- 65+: -97% (-96,-98) duction 50-64: -92% (-89,-94) 18-49: -96% (-94,-97) 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

25,000 20,460 20,000

15,000

9,140 10,000

5,000

Estimated no. cases prevented 0 Direct effects Indirect effects

CDC. MMWR Sep 16, 2005 Invasive180 Pneumococcal Disease Burden (US)

160 140 Cases

120

100

60 Cases per 100,000 per Cases 40

20000 <2 2 to 4 5 to 17 18 to 34 35 to 49 50 to 64 65 to 79 >80 1800 Age Group (Years) 1600 1400 Deaths 1200

1000

800

600 Estimated # Deaths Estimated 400

200

0 <2 2 to 4 5 to 17 18 to 34 35 to 49 50 to 64 65 to 79 >80 Robinson et al. JAMA 2001;285:1729 Age Group Rates of IPD Caused by Serotype 19A Among Adults >18 Years Old - ABCs 1998-2009

Age, Percent change Rate years (95% CI) 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 2000  Contains serotypes: Carrier protein 4, 6B, 9V, 14, 18C, 19F, 23F

 PCV13  Introduced in United States in March, 2010 Carrier protein  Contains PCV7 serotypes + 1, 3, 5, 6A, 7F, 19A Cumulative PCV6-type IPD Cases Among Children Aged <2 years, 2005-2011 Better Immunogenicity of PCV in Adults

GMC Antibody for PCV13 superior to 23vPS

18 *

14 * * 12 * 10 * Pr ev nar 8 23vPS 6 4 * 2

0 4 6B 9V 14 18C 19F 23F

PCV13 N = 110; 23vPS N = 107 * statistically significant Efficacy of PCV13 vs Community Acquired Pneumonia (CAP) in Adults (CAPITA trial1)

Reduction in Pneumococcal Disease with PCV13

0 10 20 46% 45% 75% 30 p < 0.001 p = 0.007 p < 0.001 40 50 60 Prevention of VT Prevention of VT 70 pneumococcal nonbacteremic 80 CAP pneumococcal Vaccine efficacy (%) efficacy Vaccine Prevention of 80 CAP 100 VT IPD

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

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 <5 Years (Deaths)

O’Brien Lancet 2009 Estimated Impact of Underutilized Vaccines Globally: 2011-2020

Haemophilus influenzae Type B 1.4 – 1.7M

Pneumococcus 1.6 – 1.8M

Meningococcal A meningitis 0.03M

Rotavirus 0.8 – 0.9M

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

Bill Jordan John LaMontagne Carole Heilman Pamela McInnes Prevenar R&D Team - Wyeth

Lung Hsieh Puvy Bob Corder Arum

Jim Cowell Brad Kosiba Maya Koster Bruce Green Antibody Assays are Key!

Dace Madore Sally Quatert Dan Sikkema David Goldblatt

Moon Nahm George Carlone Helena Kaythy Tim McDermott Estimating the Protective Level of Antibodies to Pneumococci (0.35 µg/ml)

100 7vPnC7vPnC with without 22F MnCC without 90 7vPnC with 22F MnCC without 22F 80 MnCC with 22F 70

50 [C]prot without 22F = Bob Kohberger

% Subjects 40 0.35µg/ml [C]prot with 22F = 0.32 30 µg/ml 20

0 0.01 0.15 0.35 1 2 4 8 16 32 64 Antibody Concentration Ih Chang

Siber et al. Vaccine. 2007 (19) 3816 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

Juhani Eskola Keith Klugman Mathu Santosham Kate O’Brien

Bill Gruber Jill Hackell Steve Lockhart Beate Thoma Clinical Study Collaborators Regulatory Approvals and Recommendations

Carolyn Hardegree Norman Baylor KarenK Midthun 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!

• Broader coverage • Simpler to make • Lower cost

Genocea Team

Affinivax Team Finally… a Special Thanks to Two of My Strongest Supporters! Developing Pneumococcal, Meningococcal and Hib Vaccines

George Siber MD CSO, ClearPath Vaccines Adjunct Professor, Johns Hopkins University Bloomberg School of Public Health

Sabin Gold Medal Ceremony 2016