S' aureus vaccine development

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S. aureus vaccine development

• Jean C. Lee, Ph.D.
• Channing Laboratory
• Brigham and Womens Hospital Harvard Medical
  School

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Why an S. aureus vaccine?

• S. aureus is the most common cause of
  hospital-acquired infections. Recently, it has
  emerged as a significant pathogen in the
  community, where it has affected hosts without
  predisposing risk factors.
• S. aureus is one of the leading causes of
  hospital-based bloodstream infections with a
  crude mortality rate 25.
• Every antimicrobial therapeutic strategy has been
  met with a resistance strategy response by the
  staphylococcus.

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Immunity to S. aureus infections

• little resistance to nasal or skin colonization
• high innate resistance to invasive staphylococcal
  infection
• epidermal/mucosal surface barriers
• intact cellular, humoral, and innate immune
  defenses
• Serious infection - dependent upon mechanical,
  immunologic, metabolic changes in host status
• Phagocytosis important - influenced by strain,
  abs, C
• Infection models - gt106 bacteria foreign
  body
• no good evidence to suggest that patients who
  recover from S. aureus infections are immune to
  re-infection.

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What infections should be targeted for
prevention?

• prosthetic device infections
• bacteremia - metastatic complications
• endocarditis
• osteomyelitis
• pneumonia
• wound infections
• Not cutaneous disease - impetigo, boils,
  folliculitis,
• toxin-mediated disease - TSS, SSS (too rare)
• food poisoning - no treatment

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Ideal vaccine

• prevents bacterial adherence
• promotes phagocytic killing
• neutralizes toxic exoproteins

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Vaccine types

• Whole bacteria
• Purified antigens - ideal
• Surface-associated
• Immunogenic in purified form
• Antigen expressed by all clinical isolates
• Limited number of serologic types
• Nontoxic
• Purified toxoids

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Vaccines in Clinical Trials
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CP5/CP8 Conjugate Vaccines

• More immunogenic than purified CP alone
• Elicit a T cell response
• Ali Fattom and colleagues at Nabi, Inc. (USA)
  linked CP5 and CP8 to nontoxic recombinant
  exotoxin A from Pseudomonas aeruginosa (rEPA)
• StaphVAX? bivalent vaccine (CP5-rEPA
  CP8-rEPA) intended for immunization of
  individuals at high risk for S. aureus infection
• Shown to have some protective efficacy in animal
  models of staphylococcal infection

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Serotype 5 Strain Reynolds
Acapsular Mutant
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Choice of end-stage renal dialysis patients as a
target population

• Advantage
• Population at a high risk (5).
• Efficacy could be shown in relatively short
  period and reasonable numbers of patients.
• Patients are well monitored and epidemiology
  established.
• Captive population (3 times/wk in dialysis
  center).
• Disadvantage
• Secondary to uremia, frequent dialysis, and
  diabetes, there is reduced immunogenicity of
  vaccines in this population
• Fast antibody decline rate
• Impaired neutrophil function
• Reduced respiratory burst
• Reduced chemotaxis

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StaphVAX phase III clinical trial

• 1998 - 2000 double-blind trial to evaluate the
  safety, immunogenicity, and efficacy of StaphVAX
  for prevention of bacteremia.
• 1800 patients with end-stage renal disease
  receiving hemodialysis .
• Half administered a placebo half immunized with
  a single injection of Nabis bivalent StaphVAX
  (100 µg each of CP5 and CP8 conjugated to rEPA).
  
• Efficacy incidence of S. aureus bacteremia over
  weeks 3 to 54 following immunization.

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StaphVAX Efficacy
NEJM 346491 (2002)
H. Shinefield, Vaccine (2005)
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StaphVAX Antibody Titers in Hemodialysis Patients
P 0.02
P 0.02
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Questions raised by Nabis CP5/8 Vaccine Phase
III trial

• Does immunization reduce S. aureus nasal
  colonization in these patients?
• Does impaired phagocyte function in these
  patients (about half are diabetic) explain why
  the estimated protective level of protective
  antibodies (gt80 µg/ml) is so high?
• Can a vaccine that only targets the capsule
  protect patients against a bacterium with such a
  multitude of virulence determinants (adhesins,
  exoenzymes, and exotoxins)?

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StaphVAX confirmatory phase III clinical trial

• Double-blind, placebo-controlled, randomized
  trial
• 3,600 end-stage renal disease patients on
  hemodialysis in 200 sites across the U.S.
• Efficacy evaluated from week 3-35. Boost with
  StaphVAX. Follow patients for 6 more months.
• November 1, 2005 Nabi announced that
  the StaphVAX Phase III confirmatory clinical
  trial failed to meet its primary endpoint.  The
  study found no reduction in S. aureus types 5 and
  8 infections in the StaphVAX group compared to
  the placebo group. 

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StaphVAX - what next??
3/21/2006 Nabi Biopharmaceuticals Announces
Completion of Outside Advisory Panel Assessment
of Gram-Positive Program Development of StaphVAX
and AltaStaph to Continue 1. The functional
characteristics of the antibodies generated by
the vaccine used in the confirmatory clinical
study was inferior to those antibodies generated
by vaccine lots used in previous and subsequent
clinical studies. 2. Medical factors associated
with kidney disease in dialysis patients impaired
their immune response to the vaccine. 3.
Increase in the virulence of the bacterium

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Altastaph by Nabi

• An investigational human antibody-based product
  that is produced by vaccinating healthy
  volunteers with StaphVAX and then harvesting the
  anti-staphylococcus antibodies.
• Developed to provide short-term, immediate
  protection to patients who either cannot wait for
  the vaccine effect to occur or whose immune
  system is too compromised to mount a response to
  a vaccine.
• The initial target patient group is very low
  birth-weight neonates who are at high risk of S.
  aureus infection because of the invasive medical
  procedures they face and their immature immune
  system.
• Other patient groups that might benefit from
  Altastaph are patients in intensive care units
  and burn units.

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Altastaph Phase II clinical study
Two IV doses 14 days apart 1000 mg/kg Altastaph
or 20 ml/kg of saline Followed 158 infants for
28 d after the second infusion or until discharge
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Surface Proteins of Staphylococcus aureus
Von Willebrand Factor
Protein A IgG
Y
Y
ClfA
MSCRAMM Microbial Surface Component Recognizing Ad
hesive Matrix Molecules
Fibrinogen
ClfB
Keratin 10
Collagen
Cna
MAP
FnBP
SdrC SdrD SdrE Bbp
Fibronectin
Fibrinogen Elastin
Bone Sialoprotein
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Novel Antibody-Based Products Targeting Microbial
Surface Components Recognizing Adhesive Matrix
Molecules (MSCRAMMs)
Passive immunotherapy Target in S. aureus is
Clumping Factor A (ClfA)
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Veronate

• Prevention of late-onset sepsis in very low birth
  weight infants
• Plasma-derived, donor-selected polyclonal IVIG
• High levels of IgG directed against MSCRAMM
  proteins
• S. aureus ClfA
• S. epidermidis SdrG
• Shows some protective efficacy in animal models
  of S. aureus infection
• Formulated for premature infants

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Veronate Phase II Trial

• Design
• Enrolled 512 very low birth weight infants
  (500-1,250g)
• 48 enrolling sites randomized, double-blind,
  placebo-controlled
• 250 mg/kg, 500 mg/kg, and 750 mg/kg (up to four
  IV administrations)
• 70 day follow-up
• Endpoints
• Preliminary estimation of biological activity
• Dose selection for Phase III
• Safety and pharmacokinetics

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Veronate - Phase II
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Veronate Phase III Trial

• Design
• 2000 very low birth weight infants (500-1,250g)
• Randomized, double-blinded, placebo controlled
• 750 mg/kg (up to four IV administrations) 70 day
  follow-up
• 80-100 NICUs in the U.S. and Canada
• Endpoints
• Primary Reduction in the frequency of S. aureus
  infections
• Secondary
• Reduction in the frequency of Candida infections
• Reduction in all cause mortality
• Reduction in the frequency of CoNS infections

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Inhibitex Reports Top-Line Results in Phase III
Study of Veronate ATLANTA, April 3,
2006 /PRNewswire-FirstCall/ -- Inhibitex, Inc.
(Nasdaq INHX) today announced that Veronate
failed to meet its primary endpoint in the
Company's Phase III clinical trial for the
prevention of hospital-associated infections due
to Staphylococcus aureus in premature infants
weighing between 500 and 1,250 grams at birth.
The Company further reported that there were no
measurable effects or trends in favor of Veronate
for the primary or any of the secondary endpoints.
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• Aurexis (tefibazumab)
• Humanized monoclonal antibody (IgG1) recognizing
  the S. aureus MSCRAMM protein ClfA
• For treatment and prevention of S. aureus
  infections

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Aurexis Planned Trial 2006

• Phase I/II Trial safety and pharmacokinetic trial
• 16 hospitalized patients with S. aureus
  bacteremia
• Two doses, IV, 20 mg/kg at a 5-day interval
• Patients will also receive standard antibiotic
  therapy

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Aurograb
NeuTec Pharma has developed genetically
recombinant antibodies, or "grabs", for the
treatment of life-threatening infections.
"Grabs" against these patented antigens are
derived (using the Company's FabTec platform
technology) from patients who recovered from
staphylococcal infection. As a result, these
"grabs" are of high specificity, affinity and
potency against the microbial target. The
company anticipates that Aurograb will be of
particular benefit when prescribed in combination
with vancomycin in the treatment of MRSA
infections, both increasing efficacy and
inhibiting the emergence of VISA.
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Aurograb has the following properties as an
anti-staphylococcal agent ? intrinsic activity
against staphylococci ? synergistic activity
with vancomycin the combined use of the two
agents together giving greater activity than
either agent alone and ? a broad spectrum of
activity against different strains of S. aureus
including the currently circulating epidemic
strains of MRSA and VISA.
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Aurograb Phase III clinical trial

• A phase IIb study which was completed in June
  2003. Aurograb was well tolerated and
  demonstrated a profile that supports likely
  activity against MRSA in man. Aurograb has
  activity on its own against strains of MRSA, but
  when combined with vancomycin, the current gold
  standard treatment, is more effective than
  either drug used on its own. The activity is also
  evident in strains with partial resistance to
  vancomycin or linezolid.
• NeuTec has commenced a double-blind
  placebo-controlled phase III clinical trial.
• The trial compares the effects of Aurograb in
  combination with vancomycin versus vancomycin
  alone in the treatment of MRSA infections.
• 35 centers in 6 European countries
• 150 adult hospitalized patients with deep-seated
  staphylococcal infections.

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S. aureus cell wall
LTA structure
D-Ala
Glucose Glucose Glycerol-P
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Human chimeric mAb from Biosynexus, Inc. Target
Lipoteichoic Acid

• Group A Streptococcus
• Major pathogen
• Toxic strep, necrotizing
• fasciitis
• Strep throat and ARF

• Enterococcus
• Nosocomial infections
• Resistant to antibiotics

• Staphylococcus
• Coag. Neg. Coag. Pos.
• Major cause of nosocomial infection
• Resistant to antibiotics

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The Multi-functional Potential of Anti-LTA
Antibodies

• Block adherence of bacteria to surfaces
• Enhance opsonization of bacteria
• Block toxic effects of LTA by inhibiting cytokine
  induction
• Showed some protection in animal models of
  staphylococcal infection

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Phase II Neonatal Study with LTA mAb(Passive
Immunization)

• Targeted Product indication
• Prevention of staphylococci sepsis in the very
  low birth weight neonate (700-1300g)
• Phase II study
• Randomized, double blinded
• 3 doses per group, Days 0, 7, and 14 of study
• 60 or 90 mg/kg
• 88 infants enrolled in first 5 days of life

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Pagibaximab (LTA mAb) Phase II Study1

• Results
• Appeared safe and tolerable
• Linear pharmacokinetics
• 90 mg/kg dose produced sustained serum levels
  gt500 µg/mL
• No staphylococcal sepsis was seen at levels gt500
  µg/mL
• Future studies
• Confirm dosing regimen to maintain pagibaximab
  gt500 ug/mL
• Evaluate pagibaximab for prevention of
  staphylococcal sepsis in high-risk neonates

1Thackray H, et al. Pediatric Academic Societies
Annual Meeting, San Francisco, April 2006
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Merck begins phase I clinical trial for S. aureus
vaccine

• Vaccine Weekly
•  2006 JAN 25 -- Intercell AG announced the start
  of a phase I clinical trial by Merck Co., Inc.,
  for a vaccine against Staphylococcus aureus
  infections based on an antigen discovered by
  Intercell's proprietary bacterial Antigen
  Identification Program (AIP).
• Evaluation of tolerability and immunogenicity of
  the 0657nI vaccine in healthy adults
• Study start March 2006
• Three different dosage levels 5, 30, or 90 µg
  IM compared to saline placebo.
• Panel A 36 subjects.
• Panel B 84 subjects
• Total 120 subjects

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Is this Mercks new vaccine candidate?
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Preclinical studies of new S. aureus vaccine
candidates
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Some efficacy in animal models of S. aureus nasal
colonization

• Clumping factor B (ClfB) - Jean Lee,
• Infect Immun 742145 (2006)
• Iron Surface Determinant B (IsdB) - Simon Foster,
  JID 1931098 (2006)

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Some efficacy in animal models of S. aureus
infection (recent)

• Poly-N-acetyl glucosamine (Gerald Pier)
• Cna-FnBP fusion protein (Zhou et al.)
• DNA vaccines - PBP2a, ClfA
• Staph A heteropolymer (Elusys Therapeutics)

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ICAAC, 2005
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Elusys Therapeutics Inc., Pine Brook, NJ, ICAAC
2005
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Elusys Therapeutics, Inc.
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Thanks to

• Ali Fattom, Ph.D., Nabi Pharmaceuticals, Inc.
• Joseph Patti, Ph.D., Inhibitex, Inc.
• Jimmy Mond, M.D., Ph.D., Biosynexus, Inc.