VACCINE RESEARCH NTERNATIONAL Plc

VACCINE RESEARCH NTERNATIONAL Plc

STAPHYLOCOCCAL VACCINES
Ahmad A; Davies J A; Ravenhill KA and Skinner GRB
Staphylococcal infection
A hospital acquired infection
In UK, Staphylococcal infections account for about one fifth of
Hospital Acquired Infections.
Staphylococci cause post-operative infections, septicaemia,
cellulitis, pneumonia and osteomyelitis and are extremely
troublesome with intra-vascular devices and catheters.
Approximately 40% are due to the antibiotic-resistant strain of
Staphylococcus aureus, MRSA.
Similar problems exist in Europe, the USA and Japan.
Hospital acquired infections
PROBLEM COSTS
UK
100,000 patients infected per year
of whom an estimated 5000 die.
1billion per year
USA
2 million patients infected per year.
10% die; approx. 14,000 die from
drug-resistant organisms.
> $4.5 billion per
year
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 staphylococcal
infections in Japan are MRSA.
STAPHYLOCOCCAL VACCINES
McCoy and Kennedy
1960
Autologous vaccine
inactivated with
benzalkoniumchloride
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 if
needed.
Recurrent
Staphylococcal skin
infectiuons in miners
eg furunculosis
12/13 Recovered
15/15 Recovered
0/12 Recovered
3/9 Recovered
STAPHYLOCOCCAL VACCINES
Salmon & Symonds
1963
Staphylococcal
bacteriophage lysate
Intranasal and in
children <2 years
administered by nose
drops on alternate
days for total of 10
days then weekly and
finally monthly
Chronic
Staphylococcal
infections eg
eczema, acne,
pyoderma, intestinal
infection, upper
respiratory infections
486/607 Recovered
110/607 Improved
11/607 Not helped
Bryant et al 1965 Staphylococcal
bacteriophage lysate
vaccine
Intramuscular
injections
Recurrent
furunculosis
No significant
difference between
vaccinated and
control groups
STAPHYLOCOCCAL VACCINES
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 placebo
controlled study
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 and
intramuscular
injections
Staphylococcal
infection and
volunteers
Rise in anti-alpha
toxin antibodies in all
vaccinated
individuals
STAPHYLOCOCCAL VACCINE
Mudd et al 1965 Panton-Valine:
leucocidin toxoid
formalised F +S
components of
leucocidin.
Divasta-Institut
Pasteur: purified
alpha toxoid +
inactivated
Staphylococci.
Staphage-Delmont
Laboratories:
Staphylococcal
bacteriophage
lysate
Patients received
leucocidin+Staphage
vaccine or Staphage
vaccine +alpha
toxoid.
Osteomyelitis and
wound infections
Vaccinated patients
did better than non-
vaccinated patients
but there were no
controls.
There was optimal
leucocidin response
in 3-5 weeks.
There was an
increase in anti-alpha
toxin response in
patients given alpha
toxoid
STAPHYLOCOCCAL VACCINE
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
STAPHYLOCOCCAL VACCINE
Weber et al 1971 Staphypan Berna:
formalin-inactivated
alpha toxin from
S.aureus +formalin-
inactivated endotoxin
from 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 antibody
levels 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
STAPHYLOCOCCAL VACCINE
Poole-Warren et al
1991
Staphypan Berna 6 intramuscular
injections of
increasing
concentration over 6
weeks. 4 Boosters
every 3 months
Prevention of
infections in
continuous
ambulatory peritoneal
dialysis
124 patients. No
difference in
peritonitis or catheter
related
Staphylococcal
infection between
vaccinated and
placebo controlled
patients
STAPHYLOCOCCAL VACCINE
Welch et al 1996 Capsular
polysaccharide type
5 conjugated to
recombinant
Pseudomonas
aeruginosa
exoprotein A
2 Intramuscular
injections at 6 week
intervals.
17 patients
24 Normal controls
Immune response in
human subjects
Increase in IgMand
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
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-binding
protein, 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.
Immunoblot using S.aureus P/DFO 75 vaccine and sera from rabbit given the vaccine at a
concentration of 5X10 tenth bacterial equivalent
Immunoblot using S.aureus P/DFO 75 vaccine and sera from rabbit given the vaccine at a
concentration of 5X10 ninth bacterial equivalent
Immunoblot using S.aureus P/DFO 75 vaccine and sera from rabbit given the vaccine at a
concentration of 5X10 eighth bacterial equivalent
Reacti vi ty of sera from femal e rabbi t 19 gi ven 5X10tenth Batch 5 vacci ne (pl ateXX)
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 dilution sera
A
b
s
o
r
b
a
n
c
e
5X10tenth Pre (19)
5X10tenth I (19)
5X10tenth II (19)
5X10tenth III (19)
5X10tenth IV (19)
CONTROL
ACKNOWLEDGEMENTS
VACCINE MANUFACTURE
NORWEGIAN INSTITUTE OF PUBLIC HEALTH, OSLO, NORWAY
REGULATORY ADVISORS
QUADRAMED, MIDHURST, WEST SUSSEX, UK
TOXICOLOGY
CTL, ALDERLEY PARK, MACCLESFIELD, CHESHIRE, UK
CLINICAL TRIAL
SIMBEC, MERTHYR TYDFIL, WALES, UK
BINDING PROTEIN EVALUATION
PROFESSOR J AN-INGMAR FLOCK, KAROLINSKA INSTITUTET,
STOCKHOLME, SWEDEN