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8/12/2019 Istorie Stafilococ

1/19

VACCINE RESEARCH NTERNATIONAL PlcVACCINE RESEARCH NTERNATIONAL Plc

STAPHYLOCOCCAL VACCINES

Ahmad A; Davies JA; Ravenhill KA and Skinner GRB


2/19

Staphylococcal infection

A hospital acquired infection

In UK, Staphylococcal infections account for about one fifth ofHospital Acquired Infections.

Staphylococci cause post-operative infections, septicaemia,cellulitis, pneumonia and osteomyelitis and are extremelytroublesome with intra-vascular devices and catheters.

Approximately 40% are due to the antibiotic-resistant strain ofStaphylococcus aureus, MRSA.

Similar problems exist in Europe, the USA and Japan.


3/19

Hospital acquired infections

PROBLEM COSTS

UK 100,000 patients infected per yearof whom an estimated 5000 die.

1bill ion per year

USA 2 mill ion patients infected per year.10% die; approx. 14,000 die fromdrug-resistant organisms.

> $4.5 bil lion peryear


4/19

MRSA

A current threat to public health

worldwide

Resistance emerging to vancomycin

MRSA now entering the general community.

A worldwide problem e.g. 70% of staphylococcalinfections in Japan are MRSA.


5/19


McCoy and Kennedy

1960

Autologous vaccine

inactivated with

benzalkonium chloride

Intracutaneous

injections 2-3

days apart.

Total of 10

injections

Recurrent skin

infections,

osteomyelitis, post

operative wound

infections

44/60 Excellent

improvement

11/60 Improvement

5/60 Failure

Angyal et al 1967 Autovaccine*

Diffuse Smith strain of

S.aureus*

Compact Smith strain of

S.aureus*

Commercial polyvalent

vaccine

Intracutaneous

injections.

5 doses at 3-4

day intervals,

1-2 more ifneeded.

Recurrent

Staphylococcal skin

infectiuons in miners

eg furunculosis

12/13 Recovered

15/15 Recovered

0/12 Recovered

3/9 Recovered


6/19


Salmon & Symonds

1963

Staphylococcal

bacteriophage lysate

Intranasal and in

children


7/19


Greenberg et al 1961 Polyvalent somatic

antigen vaccine;

mixture of dornase

lysed strains of

S.aureus

Intracurtaneous and

intramuscular

Initial human tests

induced reaction after

inoculation.

Vaccine modified by

change in growth

medium

Dillenberg & Waldron

1963

Polyvalent somatic

antigen vaccine

Intramuscular

injections; 2 doses at

6 week intervals

Impetigo Reduction in

incidence of boils and

impetigo in 90% of

vaccinated

individuals in placebocontrolled study


8/19

STAPHYLOCOCCAL VACCINE

Mudd et al 1962 Divasta-Institut

Pasteur: purified

alpha toxoid +

inactivated

Staphylococci

Sclavo:

Staphylococcal

toxoid

Connaught

Laboratories:

Staphylococcal alpha

and beta toxoid

Lederle:

Staphylococcal

toxoid

formaldehyde treated

exotoxin

Subcutaneous andintramuscularinjections

Staphylococcalinfection andvolunteers

Rise in anti-alpha

toxin antibodies in all

vaccinated

individuals


9/19


10/19


Rossi & Candiani

1983

Killed heptavalant

vaccine

Intramuscular

injections. 2 doses 2

days apart of high

antigen content

vaccine +Pseudomonas

aeruginosa vaccine

given at the same

time

Wound infections in

burns

Reduction in burn

infections but no

significant reduction

in septicaemias


11/19


Weber et al 1971 Staphypan Berna:

formalin-inactivated

alpha toxin from

S.aureus + formalin-

inactivated endotoxinfrom S.epidermidis +

heat and formalin

inactivated S.aureus

and S.epidermidis in

0.01% Thiomersal

Subcutaneous

injections every 3

days 2-3 weeks prior

to surgery to allow

optimal antibodylevels to coincide

with operation

Prevention of infection of

prosthetic hip replacement

863 patients

1967-1970.

Infection rate

reduced from

6.8% to 0.45%

Scatizzi et al 1988 Staphypan Berna 6 intramuscular

injections of

increasing

concentration on

alternative days.

Booster every 1-3

months

Prevention of infection in

continuous ambulatory

peritoneal dialysis patients

20/22 No

S.aureus

peritonitis

1/20

S.epidermidis

peritonitis

22/22 No

catheter related

Staphylococcal

infection


12/19


Poole-Warren et al

1991

Staphypan Berna 6 intramuscular

injections of

increasing

concentration over 6

weeks. 4 Boostersevery 3 months

Prevention of

infections in

continuous

ambulatory peritoneal

dialysis

124 patients. No

difference in

peritonitis or catheter

related

Staphylococcalinfection between

vaccinated and

placebo controlled

patients


13/19


Welch et al 1996 Capsular

polysaccharide type

5 conjugated to

recombinant

Pseudomonasaeruginosa

exoprotein A

2 Intramuscular

injections at 6 week

intervals.

17 patients

24 Normal controls

Immune response in

human subjects

Increase in IgM and

IgG, declining by

35% in 6 months in

patients and 9% in

normal controls.

Nasal carriage of

S.aureus reduced

from 8/17 to 3/13 in 6

months

Shinefield et al 2002 Capsular

polysaccharide type

5 and 8 conjugated to

recombinant

Pseudomonas

aeruginosa exotoxin

A

Single intramuscular

injection

Double blind placebo

controlled trial in

patients with end

stage renal disease

Increase in antibody

levels against

capsular

polysaccharide types

5 and 8 in vaccinated

patients.

Reduction in

S.aureus

bacteraemias in

vaccinated patients

up to 40 weeks post

vaccination


14/19

VRI STAPHYLOCOCCAL VACCINE

ISOLATE

1. Staphylococcus aureus P/DFO75

2. Isolate from the peritoneal fluid of a CAPD patient with peritonitis

3. S.aureus P/DFO 75 is positive for collagen-binding protein, fibronectin-bindingprotein, fibrinogen-binding protein

VACCINE

The vaccine is prepared by chloroform-inactivation of a liquid culture of S.aureus

P/DFO 75. The bacteria are washed after treatment and the inactivated whole

bacteria constitute the vaccine preparation.


15/19

Immunoblot using S.aureus P/DFO 75 vaccine and sera from rabbit given the vaccine at a

concentration of 5X10 tenth bacterial equivalent


16/19


concentration of 5X10 ninth bacterial equivalent


17/19


concentration of 5X10 eighth bacterial equivalent


18/19

Reactivity of sera from femal e rabb it 19 given 5X10tenth Batch 5 vaccine (plateXX)

11.3.2004

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 2 4 6 8

Log d ilution sera

Absorban

ce

5X10tenth Pre (19)

5X10tenth I (19)

5X10tenth II (19)

5X10tenth III (19)

5X10tenth IV (19)

CONTROL


19/19

ACKNOWLEDGEMENTS

VACCINE MANUFACTURENORWEGIAN INSTITUTE OF PUBLIC HEALTH, OSLO, NORWAY

REGULATORY ADVISORSQUADRAMED, MIDHURST, WEST SUSSEX, UK

TOXICOLOGY

CTL, ALDERLEY PARK, MACCLESFIELD, CHESHIRE, UK

CLINICAL TRIALSIMBEC, MERTHYR TYDFIL, WALES, UK

BINDING PROTEIN EVALUATION

PROFESSOR JAN-INGMAR FLOCK, KAROLINSKA INSTITUTET,STOCKHOLME, SWEDEN

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