Annaliesa S Anderson PhD FAAM

Pfizer Vaccine Research and Development

Disclosure: ASA is employed by Pfizer and previous employee of Merck. ASA owns stock in both companies

Staphylococcus aureus Vaccines

Outline

Medical need

Vaccine Development

Technical and Clinical Assessment

Challenges Associated with Vaccine Development

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Medical Need for a S. aureus Vaccine

S. aureus is a leading cause of morbidity and mortality in both healthcare-associated and community settings1

1Allegranzi et al. Lancet 2011: 377: 228-41

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Medical Need for a S. aureus Vaccine

Populations at risk include the elderly, patients with comorbidities including, renal disease diabetes and obesity, surgical patients and neonates2,3,4,5,6

Important cause of invasive disease in the under 5s in LMICs

1Lowy FD. NEJM 1998; 339: 520; 2 Klevens et al. JAMA 2007; 298: 1763; 3Noskin et al. Clin Infect Dis 2007; 45: 1132; 4David et al. Clin Microbiol Rev 2010; 23:616; 5Anderson et al. Infect Control Hosp Epidemio 2008; 29: 832

Population Region(s) Time period (yr)

Incidence per 100,000

person-years for all S.

aureus isolates

(incidence for MRSA

isolates)a

All USA 2004–2005 NA (31.8)

All, military USA 2005–2010 4.7 (2)

Children ≤20 yr of age Denmark 1971–2000 4.5–8.4 (NA)

Children ≤18 yr of age Calgary 2000–2006 6.5 (0.05)

Children <5 yr of age Kenya 1998–2002 27 (NA)

Children <15 yr of age Mozambique 2001–2006 48 (4.3)

Children <5 yr of age Ghana 2007–2009 630 (105)

Children <13 yr of age South Africa 2005–2006 26 (10)

Distribution of MSSA and MRSA in Asian and African Countries (n=623)

MSSA

MRSA

Isolates were collected collected between 2004 or 2009-10 as

part of the T.E.S.T surveillance trial.

The pie chart sizes are relative to the total number of

contributed isolates.

(Collaboration with Sanger and the University of St Andrews)

US EU LATAM

n=516 n=501 n=370 5

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Challenges in Measuring BoD of S. aureus in LMICs

Lack of surveillance infrastructure

Inconsistency in surveillance measures

Lack of trained personnel to prevent transmission and/or identify infection

Existence of factors related to lower income levels (e.g. sanitation) that foster transmission

Resources focused on other infectious diseases (e.g. HIV, malaria)

S. aureus Vaccines Update

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S. aureus Presents a Large Unmet Medical Need With a Diverse Disease Spectrum

• ~30% adults colonized3

• ~82% bacteremia due

to colonizing strain4

9.6 million abscess or

cellulitis cases diagnosed

in ambulatory settings in

US (2005)5

Hemodialysis patients

Nursing home residents

Skin and Soft Tissue Infection (SSTI)

Carbuncle, impetigo, cellulitis, wound/burn infection, abscess, SSI

Deep Infection

Surgical site infection (SSI)

Arthritis, mediastinitis, osteomyelitis,

Device-related, pneumonia,

Bloodstream Infection (BSI)

Carriage/Colonization

Anterior nares, oropharynx, GI, skin, vagina

Metastatic

Infection Endocarditis,

osteomyelitis,

device- related

1 Yu H, et al. ICAAC 2012 2 Styers D, et al. Ann Clin Micro Antimicrob 2006; 5:2 3 Kuehnert MJ, et al. J Infect Dis 2006; 193:172-9 4 von Eiff C, et al. N Engl J Med 2001; 344:11-6 5 Hersh AL, et al. Arch Intern Med 2008; 168:1585–91

• 190,000 invasive SA infections in the US annually1,2

• 260,000 SA wound infections annually3

• 180 SA SSI per 100,000 NHSN surgical procedures3

• 20,000 deaths due to S. aureus in the US annually4

• 32 M surgeries in the US annually5

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S. aureus is a Challenging Vaccine Target

Highly successful commensal organism (25-33% of humans colonized)1,2

Diverse array of virulence factors facilitate colonization and evasion of host immune response3,4

Toxins

Adhesion factors

Nutrient scavenging

Capsular polysaccharides to evade phagocytosis

Antibody and complement interference factors

Most humans fail to generate functional antibodies against S. aureus following natural infection4

No existing correlate for protection

Extensive strain diversity3

1Kluytmans et al. Clin Microbiol Rev 1997; 10: 505; 2Lowy FD. NEJM 1998; 339: 520; 3Liu, GY.

Pediatric Research 2009; 65: 71R; 4Scully et al. Fronteirs in Immunology 2014; 5: 1

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Principles of Vaccine Antigen Discovery and Validation

3. Optimize vaccine design/formulation

• Valency and coverage of pathogenesis mechanisms

• Importance of antigen modifications (lipidation, acetylation) • Dose level and need for adjuvants

2. Target validation

• Conserved?

• Expressed in diverse strains?

• Quality of immune responses?

• Effective in animal models

mimicking human disease?

1. Target identification

• Virulence factors

• Capsular polysaccharide

• Membrane protein

• Toxins

Distribution of S. aureus Lineages in Asian and African Countries (n=623)

CC5

CC8

Other

US EU LATAM

n=516 n=501 n=370 (Collaboration with Sanger and the University of St Andrews)

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Distribution of Vaccine Antigens in US Clinical Isolates

Vaccine

Candidate Description Distribution

CP5 and CP81,2 Surface-associated capsular polysaccharides cap operon is present in 99% of the isolates

ClfA3 Surface-associated clumping factor A protein clfA is present in 100% of the isolates

ClfB4 Surface-associated clumping factor B protein clfB is present in ~ 98% of the isolates

MntC5 Surface-associated Manganese transporter protein C mntC is present in 100% of the isolates

α-toxin (AT)6,7 Secreted protein hla is present in ~ 90% of isolates

FhuD27 Surface ferric hydroxamate uptake lipoprotein fhuD1 present in 100% of the isolates

Csa1A7 Surface putative staphylococcal antigen 1A lipoprotein csa1A is present in ~ 50% of isolates

EsxA7 Secreted protein through the ESAT-6 secretion system

(ESS) of S. aureus

esxA is present in ~ 99% of the isolates

EsxB7 Secreted protein through the ESAT-6 secretion system

(ESS) of S. aureus

esxB is present in ~ 80% of the isolates

PVL8,9 Secreted Panton-Valentine leukocidin, associated with CA-

MRSA

PVL genes detected in ~ 30% of the isolates

SEB10 Secreted Enterotoxin B, superantigen seb is present in ~ 20% of the isolates

1 Fattom AI, et al. Infect Immun 1996; 64:1659–65 2 Lee JC, et al. Infect Immun 1997; 65:4146–51 3 Vernachio J, et al. Antimicrob Agents Chemother 2003; 47(11):3400-6

4 Schaffer AC, et al. Infect Immun 2006; 74: 2145–53 5 Anderson AS, et al. J Infect Dis 2012; 205(11):1688-96

6 Ragle BE, et al. Infect Immun 2009; 77: 2712–18 7 Bagnoli F, et al. Proc Natl Acad Sci USA 2015; 112(12):3680-5 8 Brown EL, et al. Clin Microbiol Infect 2009; 15(2):156-64 9 Voyich JM, et al. J Infect Dis 2006; 194(12):1761-70 10 Stiles BG, et al. Infect Immun 2001; 9:2031-36

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S. aureus Clinical Development Pipeline

• First test in

humans

• Safety &

tolerability

• Immunogenicity

(functional)

• Dose level &

formulation finding

• Processes &

assays being

finalized

• Preliminary

efficacy

assessment

• Efficacy testing

• Final processes defined

• Analytical/serological/

diagnostic assays

validated

Discovery Early

Development Phase 1 Phase 2

• Antigen target

validation

• Early process

development

• Analytical assay and

formulation

development

• Serological assays

measuring functional

immune response

• Diagnostic assays

• Preclinical toxicology

Phase 3

5 1 0

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The Pathway to Developing a Prophylactic S. aureus Vaccine Has Yet to Be Successful

Vaccine Composition Efficacy Studies

StaphVAX® CP5/CP8

Conjugates

2 x Phase III studies

Hemodialysis patients1,2,3

V710 IsdB Phase II/III Cardiothoracic

surgery4

• Vaccine composition did not take all the relevant S. aureus

pathogenic mechanisms into consideration.

• Vaccines had limited ability to generate the appropriate

functional antibodies.

• Choice of clinical study populations for initial efficacy

assessments. 1 Shinefield H, et al. NEJM 2002; 346(7):491-6 2 Fattom A, et al. Vaccine 2004; 22:880-7 3 Matalon A, et al. ISSI. Lyon, France 2012 (P 09 114) 4 Fowler VG, et al. JAMA 2013; 309(13):1368-78

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S. aureus Vaccines in Clinical Development

Vaccine Sponsor Composition Development

Phase

4-component

S. aureus vaccine4 GSK

CP5 and CP8 conjugated to tetanus

toxoid (TT), detoxified AT and ClfA

Adjuvant: with or without adjuvant AS03B

Phase 1

4C-Staph5,6 GSK

(Novartis)

Detoxified AT, FhuD2 and Csa1A,

EsxAB

Adjuvant: aluminum hydroxide

Phase 1

STEBVax8 IBT/NIAID Recombinant non toxic rSEB Phase 1

NDV-3A (formerly

NDV-3)9

NovaDigm

Therapeutics

A recombinant candidal surface

glycoprotein antigen Als3p

Adjuvant: aluminum hydroxide

Phase 1

AV0328 Alopexx dPNAG conjugated to TT Phase 1

SA4Ag1,2,3 Pfizer

CP5 and CP8 conjugated to CRM197,

mutated recombinant rmClfA, MntC

Adjuvant: none

Phase 2b ongoing

1 Frenck RW Jr., et al. IDWeek 2014; 1 (suppl 1): S25 2 Scully I, et al. Surg Infect (Larchmt) 2015;. 16 (Suppl 1): S-30 3 Creech CB, Frenck RW Jr., et al. IDWeek 2015; 2 (suppl 1): S36 4 Levy J, et al. Hum Vaccin Immunother 2015; 11(3):620-31 5 Bagnoli F, et al. Proc Natl Acad Sci USA 2015; 112: 3680-85

6 Torre A, et al. Infect Immun 2015; 83: 3157-63 7 Wacker M, et al. J Infect Dis 2014; 209: 1551-61 8 Chen WH, et al. Clin Vaccine Immunol 2016; Accepted Online 5 October 2016 9 Schmidt CS, et al. Vaccine 2012; 30: 7594-7600 10 Cywes-Bentley C. et al. Proc Natl Acad Sci USA 2013; 110 (24):2209–18

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CP5 Opsonophagocytic Titers After a

Single Dose

SA4Ag Designed to Target Four Key Virulence Factors and Induce Rapid Functional Antibody Responses

Target

Antigens

Virulence

Mechanism

Functional

Immunoassay

Capsular

polysaccharide

s

(CP5 and

CP8):

CP5-CRM197,

CP8-CRM197

Immune

evasion:

Anti-

phagocytic

OPA

Clumping

factor A (ClfA):

rmClfA

Adhesion to

host factors cLIA, FBI

Manganese

transporter C

(MntC): rP305A

Nutrient

acquisition cLIA

CP=Capsular Polysaccharide; ISA=Invasive S. aureus; FBI=fibrinogen binding inhibition; cLIA=competitive Luminex immunoassay;

100

1000

10000

100000

0 60 120 180 240 300 360

GM

T (

95

% C

I)

Day

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The Elective Spinal Fusion Surgical Population was Selected for Phase 2b Based on Fulfillment of Several Efficacy Trial Design Requirements

ILLUSTRATIVE

Legend Fulfills criterion Does not fulfill criterion Partially fulfills criterion

Criteria for Identifying Target Trial Population

At-Risk

Population for

S. aureus

Relatively

immunocompetent

population

Well-defined

population

Predictable

timing of invasive

S. aureus

infection

Sufficient window

of administration

(10-60 days) prior

to surgery

Relatively high

incidence of

invasive

S. aureus

Elective Orthopedic

Surgery

Emergent

Orthopedic Surgery

Cardiothoracic

Surgery

ESRD

Diabetes

Military

Burn Patients

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Incidence and Timing of Invasive S. aureus Infections at 90 Days Postsurgery Among Adults (>18 Years of Age) by Orthopedic Procedure Type

Total Surgical

Discharges Total S. aureus Infections Total ISA Infections

Days to ISA

Infection

N

%

Inpatient N % 95% CI N % 95% CI Median

Inter-

quartile

Rangea

Spinal

Spinal fusion 84,547 90.3 721 0.85 0.79, 0.92 351 0.42 0.37, 0.46 21 15.0, 36.0

Spinal refusion 3044 99.8 32 1.05 0.74, 1.49 15 0.49 0.29, 0.82 24 12.0, 47.0

>level b 7519 100.0 NA NA NA 108 1.44 NA 18 NA

Laminectomy 52,057 47.4 394 0.76 0.69, 0.84 190 0.36 0.32, 0.42 18 13.0, 32.0

Other Orthopedic

Hip prosthesis 83,335 99.9 642 0.77 0.71, 0.83 316 0.38 0.34, 0.42 25 18.0, 38.0

Knee prosthesis 156,785 99.4 753 0.48 0.45, 0.52 380 0.24 0.22, 0.27 30 19.0, 49.5

Other joint fusion 14,290 19.6 145 1.01 0.86, 1.19 57 0.40 0.31, 0.52 29 21.0, 56.0

a. Interquartile range=25 percentile to 75 percentile

b. Data from a prior study of same Premier database (large claims database linked to microbiology data) and with slightly

different time frame (01 January 2010 to 31 December 2014). STRIVE study population was approximated including index

procedure requirements and all inclusion and exclusion criteria based on available claims and microbiology data.

Total S. aureus infections was not an outcome of this study. Premier Healthcare Database 01 July 2010 to 30 June 2015.

Procedural Risk Factors are Similar Across Elective Surgical Procedures

Total Knee

Arthroplasty

Total Hip

Arthroplasty

Instrumented

Spinal Surgery

Procedural

overview

dermis dissects between the muscles, tendons,

and nerves to reach the joints/bone

Implant

material Yes

Incision

length Variable 2 to >12 inches

Mean OR

time(min)

[+/-SD]

96.9 [37.9]1 97.6 [42.9]2 196.6 [SD NA]3

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BMP=bone morphogenetic protein; in=inches; OR=operating room.

1. Belmont et al. ACS NSQIP: 2006-2011. 2. Duchman et al. J Bone Joint Surg Am 2014. NSQIP: 2005-2011.

3. McCutcheon et al. SPINE 2014;40(14):1122-31.

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~6,000 total subjects

18 to 85 years Phase 2b/3

(case accrual)

Elective, open, posterior, spinal

fusion with multilevel instrumentation

US, Canada, Europe, Japan,

STRIVE Study Design – Ongoing

Primary Outcome

Number of subjects in each treatment group with postoperative S. aureus

bloodstream infections and/or deep incisional SSI or organ/space SSI occurring

within 90 days of elective posterior instrumented spinal fusion

2,600 total subjects

18 to 85 yr Phase 2b

Elective, posterior instrumented, spinal fusion procedures

US, Canada, Europe, and

Japan

SA4Ag Placebo (Saline)

Single IM administration 10 to 60 days

prior to surgery

Double-blind

Placebo-controlled

Study

Challenges for Developing a

S. aureus Vaccine

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Preclinical Challenges

Target of bacterial virulence factors that are essential to the pathogenesis of the organism

What are relevant antigens: single vs multiple

Relevant animal models that may predict response/efficacy in humans

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Immunological Challenges

Incomplete understanding of host immunity needed to confer protection

Lack of known correlate/s of protection

Assessment of immune response in humans: functional and/or killing antibodies

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Development Challenges

Dynamic and dramatic changes in epidemiology of SA infection

Surveillance systems targeting MRSA only

Prior vaccine failures in phase 3 clinical programs add additional obstacles

Clinical endpoints requirements

Identification of the right population for efficient assessment of VE

Relatively high S. aureus infection rate

Immunocompetence

Ability to vaccinate prior to period of risk

S. aureus disease presents during a predictable time

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Summary

Medical need

S. aureus causes a broad range of diseases in different populations

Comprehensive disease data is limited in all regions

Vaccine Development

Technical feasibility

‒ Preclinical data has not been predictive of efficacy

‒ Correlates are not available

‒ Multi antigen formulation that neutralize key virulence mechanisms is likely important

Clinical development feasibility

‒ Despite the recognized medical need, clinical populations are not straightforward

Thank you to

Naglaa Mohamed

Lisa Weiss

Alvaro Quintana

Alejandra Gurtman

David Swerdlow

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