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