Pneumococcal vaccination in UK: an update Dr Richard Pebody Immunisation Department Health Protection Agency Centre for Infections
Leading infectious causes of mortality, 2000 WHO estimates 3.5 Deaths (millions) 3.5 3.0 2.5 2.0 1.5 1.0 2.7 2.2 < 5 years old > 5 years old 1.7 S. pneumoniae: ~1.6 million deaths, including ~800,000 child deaths 1.1 0.9 0.5 0 Pneumonia AIDS Diarrhoea TB Malaria Measles Source: WHO 2
Annual incidence per 100,000 of invasive pneumococcal infection E&W, by age group and year, 1996-2000 60 50 40 Inability to to mount immune response to to capsule 1996 1997 1998 1999 2000 30 20 10 0 Waning immunity Non-immune factors 3 0-2 mths 3-5 mths 6-11 mths 12-23 mths 24-35 mths 36-47 mths 48-59 mths 5-9 yrs 10-14 yrs 15-19 yrs 20-24 yrs 25-29 yrs 30-34 yrs 35-39 yrs 40-44 yrs 45-49 yrs 50-54 yrs 55-59 yrs 60-64 yrs 65-69 yrs 70-74 yrs 75+ yrs
Burden of Pneumococcal disease Hospital Episode Statistics (HES) England Admission rate per 100,000 population/year 800 700 600 500 400 300 200 100 0 Lobar pneumonia (HES-first diagnosis) Lobar pneumonia (HES-any diagnoses) IPD (HES-first diagnosis) IPD (HES-any diagnoses) IPD lab data) 0-4 Source: Melegaro et al 5-9 10-14 15-24 25-44 45-59 60-64 Age group 65-69 70-74 75-79 80-84 85+ 4
Proportion of hospitalised pneumococcal cases reporting co-morbidity (1, 2-4 and 5+ diagnoses) Proportion of hospital admissions 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 5+ diagnoses 2-4 diagnoses 1 diagnosis <1 mths 1-11 mths 1-4 5-9 10-14 15-44 45-64 65-74 75+ Age group Source: Melegaro et al
Case-fatality ratio by age of IPD, pneumococcal pneumonia and lobar pneumonia Case-fatality ratio 45% 40% 35% 30% 25% 20% 15% 10% 5% Pnc meningitis and septicaemia Pnc pneumonia Lobar pneumonia Pnc confirmed 0% <1 mths 1-11 mths 1-4 5-14 15-44 45-64 65-74 75+ Source: Melegaro et al Age group 6
Burden of Pneumococcal disease GP consultation rate for CAP and OM 80,000 7,000 OM episode rate per 100,000 population/year 70,000 60,000 50,000 40,000 30,000 20,000 10,000 Otitis media (High risk) Otitis media (Non high risk) Pneumonia (High risk) Pneumonia (Non high risk) ` 6,000 5,000 4,000 3,000 2,000 1,000 Pneumonia episode rate per 100,000 population/year 0 0 0 Source: Melegaro et al 2 4 10-14 20-24 30-34 40-44 Age group 50-54 60-64 70-74 80-84 7
Pneumococcal polysaccharide vaccine Produced from purified capsular polysaccharide; Current vaccine contains 23 of the serotypes responsible for disease; Protects against invasive disease: BUT poor antibody responses in young children; do not induce immunologic memory, short term protection; hyporesponsiveness on revaccination do not protect against non-invasive diseases e.g. otitis media; do not reduce nasopharyngeal carriage.
Pneumococcal conjugate vaccines Pneumococcal conjugate vaccine contains 7 of the serotypes responsible for disease; Seek to prevent invasive and non-invasive (pneumonia and otitis media) disease. effective in young children; induce long-term memory; reduce Pnc carriage and induce herd immunity. 9
Coverage of vaccine serotypes in England and Wales by age: 7-valent conjugate and 23-valent polysacc vaccine Vaccine <5yrs 5-64 yrs 64+ yrs 7-valent 74.2 42.3 55.4 (85.8) (51.2) (66.9) 23-valent 97.4 96.2 96.3 Figures in ( ) based on assumption of full cross protection between serotypes within serogroups 10
Evolution of pneumococcal vaccination strategy in England and Wales Polysaccharide vaccine (23-valent) licensed in 1989: 1992 until 2003 recommended for risk groups >2 year olds post 2003 also recommended for elderly (>65 years) Conjugate vaccine (7-valent) licensed in 2001: post 2002 recommended for risk groups <2 years old post 2004 recommended for risk groups <5 years old post 2006 recommended for all infants
Risk groups for whom vaccine indicated asplenics (including sickle cell & coeliac disease); chronic lung disease; chronic heart disease; chronic renal disease; chronic liver disease (including cirrhosis); diabetes mellitus; immunocompromised (disease or treatment); HIV infection (at any stage); persons with cochlear implants. 12
Meta-analysis of polysaccharide vaccine efficacy for IPD (Melegaro et al. 2004 ) Study [Fig. 2a] Odds ratio (95% CI) Study [Fig. 2b] Odds ratio (95% CI) Klastersky,RCT (1986) 0.80 (0.05,13.60) Honkanen,QRCT (1999) 0.37 (0.07,1.91) Simberkoff,RCT (1986) 2.01 (0.18,22.20) Gaillat,QRCT (1985) 0.27 (0.01,6.54) Leech,RCT (1987) 3.20 (0.13,79.47) Ortqvist,RCT (1998) 0.21 (0.02,1.77) Overall (95% CI) 0.35 (0.08,1.49) Overall (95% CI) 0.80 (0.22,2.88) 1 Odds ratio 1 Odds ratio Little or no evidence of efficacy against pneumonia (not shown) Limited evidence for efficacy against IPD in non-high risk individuals (lefthand panel & other studies) Little or no evidence of efficacy against IPD in high risk population (right hand panel)
Polysaccharide vaccine coverage in high-risk population and all elderly >65 years, General Practice Research Database, 1989-2003 100% 90% % Vaccinated 80% 70% 60% 50% 40% 30% 20% 10% 0% % high risk vacc % all vacc 14
New polysaccharide programme for the elderly, England and Wales from 20th August 2003: all people > aged 80 years from 1st April 2004: extended to all > aged 75 years from 1 st April 2005: extended to all > aged 65 years 15
Enhanced pneumococcal surveillance PPV coverage: 10 year historical coverage & previous 12 months uptake from GPs From August 2004 for 80+ From April 2005 for 75-79 From April 2006 for 65-74 Enhanced IPD surveillance: All serotyped IPD cases followed with GP to ascertain: - immunisation history; - outcome of infection; - underlying risk factors. 16
US pneumococcal conjugate vaccine efficacy trial: 2/4/6 months + 12 month booster PCV efficacy against Invasive disease vaccine serotypes (ST) 97.4% Invasive disease vaccine ST 1+ dose 85.7% Lobar pneumonia 73% Any pneumonia with abnormal CXR 33% Any otitis media episode 8.9% Recurrent OM 11.9% Ear tube placement 20.1% 17
Finnish Prevenar Efficacy Trial against Serotype-specific Culture-confirmed Acute Pneumococcal Otitis Media (AOM) in Infants and Children Episodes due to vaccine related serotypes 51% (27 to 97) Any culture confirmed pneumococcal AOM 34% (21 to 45%) AOM irrespective of aetiology 6% (-4 to 16%) Episodes due to non-vaccine serotypes - 33% (-80 to 1) Eskola J, et al NEJM 2001
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Design of infant trial, UK PCV/PPV given concomitantly with DTaP 3 /Hib- TT + MCC- CRM 9V Conj at 2mths 9V Conj at 3 mths 9V Conj at 4 mths 23V Poly at 1yr 9V Conj at 1yr 20
7 6 5 Serotype-specific IgG GMCs after 3 doses (at 2/3/4 months) or 2 doses (at 2 and 4 months) of conjugate in UK infants compared with USA schedule* 3 dose 2 dose USA ug/ml 4 3 2 1 0 4 6B 9V 14 18C 19F 23F 1 5 pneumococcal serotype Source: Miller et al. *Data from Black et al PIDJ 2000 21
Vaccination schedule in the UK 2006 Primary immunisation 2 months Diphtheria-tetanus-acellular pertussis, inactivated polio vaccine and Haemophilus influenzae type b Pneumococcal conjugate vaccine 3 months Diphtheria-tetanus-acellular pertussis, inactivated polio vaccine and Haemophilus influenzae type b Meningococcal group C conjugate 4 months Diphtheria-tetanus-acellular pertussis, inactivated polio vaccine and Haemophilus influenzae type b Meningococcal group C conjugate Pneumococcal conjugate vaccine DTaP-Hib-IPV PCV DTaP-Hib-IPV MenC DTaP-Hib-IPV MenC PCV 13 months Measles-mumps-rubella MMR 22
Vaccination schedule in the UK 2006 (continued) Booster immunisation 12 months Haemophilus influenzae type b Meningococcal group C conjugate Hib-MenC 13 months Pneumococcal conjugate vaccine PCV 3½-5 years Diphtheria-tetanus-acellular pertussis and inactivated polio vaccine DTaP-IPV or dtap/ipv Measles-mumps-rubella MMR 13-18 years Tetanus-low dose diphtheria and inactivated polio vaccine Td-IPV 23
Cumulative Weekly Number of Reports of Invasive Pneumococcal Disease Due To One of the Serotypes Not Present in Prevenar for Children Aged 0-2 Years in England and Wales by Epidemiological Year: July - June (2003 to Date) 24
Cumulative Weekly Number of Reports of Invasive Pneumococcal Disease Due To One of the Seven Serotypes Present in Prevenar for Children Aged 0-2 Years in England and Wales by Epidemiological Year: July-June (2003 to Date) 25
Current issues Impact and effectiveness of current programme Pneumococcal clusters Emergence of non-7-valent PCV serotypes Pneumococcal vaccine development: 10-valent and 13-valent vaccines in advanced stages of testing At least one common protein candidate approaching large-scale clinical evaluation 26
Acknowledgments Prof. Liz Miller and the staff in the HPA Immunisation Dept especially Pauline Kaye, Usha Gungabissoon, and Nick Andrews; Dr Robert George, Dr Mary Slack and Siobhan Martin and all staff of the HPA Streptococcus and Diphtheria Reference Unit, RSIL; Dr Alessia Melegaro, John Edmunds and colleagues of the HPA Modelling and Economics Department; Prof. David Goldblatt of the Institute of Child Health, London Microbiologists, and General Practitioners across the country for referring IPD isolates, reporting infections and responding to all our (numerous) information requests. 27