2. Pneumococcal Vaccine in Children Dr. Kwan Yat-wah Department of Paediatrics and Adolescent Medicine Princess Margaret Hospital

3. Streptococcus pneumoniae ( Pneumococcus) Gram Positive,  -hemolytic encapsulated diplococcus Polysaccharide capsule define the serotype – 91 distinct capsular types –Welcome 6C # Prevalence spectrum varies with age, geographical region # Park IH. Discovery of a New Capsular Serotype (6C) within Serogroup 6 of Streptococcus Pneumoniae. Journal of Clinical Microbiology 2007; 45:1225-1233

4. The Pneumococcus Major cause of respiratory disease and bacterial meningitis worldwide

5. Invasive Pneumococcal Disease (IPD) Case Definition: –Isolation of Streptococcus Pneumoniae from a normally sterile site (not including middle ear) or –Demonstration of Streptococcus Pneumoniae antigen in Cerebrospinal Fluid

6. Invasive pneumococcal disease (IPD) –Pneumonia with bloodstream infection, septicemia, meningitis Localized respiratory disease –Middle ear infections, sinusitis, bronchitis, pneumonia

7. Capsule Polysaccharide Define the virulence The main target of vaccine intervention

8. Epidemiology

9. Very common in the very young and very old Reservoir: Human, colonization in the upper respiratory tract of healthy people Transmission:Respiratory droplets, direct oral contacts, indirectly through articles freshly soiled with respiratory discharges Incubation Period: 1-3 days

10. Invasive Pneumococcal Disease Incidence by Age Group England and Wales 2000 (pre-PCV7) Health Protection Agency Communicable Disease Surveillance Centre. CDR Weekly 2003; 12(21) Germany: 8.9 per 100,000 children; Switzerland: 7.6 per 100,000 children England and Wales: 14.5 per 100,000 children

11. Nasopharyngeal carriage Gambia:76.1 – 85.1 Pakistan:51.9 – 64.4% Philippines:51 – 62% South Africa:29.4% Southern Israel:35% - 93% Uruguay:15.2 – 42.1% Zambia:71.9%

12. Nasopharyngeal carriage of Pneumococcus 10 20 30 40 50 PreschoolGrammar school Jr. High School Carriage rate (%) 60 60% 35% 25% 0 Households with children Households without children 29% 6% 1 Presentation by Mark A. Fletcher, M.D., on Epidemiology of Streptococcus pneumoniae: “Pneumococcus”

13. Burden of Pneumococcal Disease

14. Pneumonia Largest infectious Disease Causes of Child Death Worldwide* Can be bacterial / viral, but the 1 st cause if Streptococcus Pneumoniae –Responsible for >1 million child deaths annually In developed countries, high morbidity (empyema,..) and adult carries most of the burden of the disease * UNICEF 2006: Pneumonia, the forgotten killer of children WHO 2003; Levine 2006

15. Burden of Pneumococcal Disease Overall burden is difficult to estimate Problems inherent in establishing bacterial etiology in people with pneumonia, bacteraemia, meningitis or otitis media

16. Prevalence of IPD varies with Geographical region Risk Factors: –Age –Underlying diseases –Ethnic Groups

17. Incidence of IPD in children < 2yrs old Robinson KA JAMA 2001; Davidson M JID 1994; O’Dempsey TJ PIDJ 1996: Levine MM PIDJ 1998; Cortese MM Arch Intern Med 1992; Torzillo PF Med J Austr 1995; Eskola J JAMA 1992; Berkley NEJM 2005 Argentina 206.8 HONG KONG 18.9 UK 37.1-48.1 Australia 96.4 150 South California

18. Young Children – High Risk Risk factors for IPD are: –Children < 2 years of age –Underlying disease –Children who attend daycare in previous 3 months Risk factors for penicillin-resistant IPD –Children exposed to > 1 course of antibiotics –Children with history of > 1 recent ear infection in previous 3 months OS Levine, M Farley, et. al. Risk factors for Invasive Pneumococcal Diseases in Children: A Population-Based Case-Control Study in North America. Pediatrics 103; 3: 1999

19. A Finnish study (children < 2 years) who –attended daycare provided outside the home had a 36-fold  in risk of IPD –attended family daycare had a 4.4-fold 

20. Risk for IPD AgePer 100 000 6-11 months235 < 12 months205 < 23 months165 Ethnicity African American>400 Native American, Native Alaskan 557 – 2400 Australian Aborigine170 Splenic Dysfunction600-6500 HIV Infection587-11300

21. Invasive Pneumococcal Disease Incidence by Age Group England and Wales 2000 (pre-PCV7) Health Protection Agency Communicable Disease Surveillance Centre. CDR Weekly 2003; 12(21) Germany: 8.9 per 100,000 children; Switzerland: 7.6 per 100,000 children England and Wales: 14.5 per 100,000 children

22. Situation in Hong Kong

23. Annual incidence of culture-confirmed IPD, Hong Kong Island, by age, 1995-2004. Invasive pneumococcal disease (IPD) based on all positive cultures (blood, CSF, body fluid) in two major hospitals (Queen Mary Hospital and PYH) representing 90% of all cases on Hong Kong island, 1995-2004. Population figures from sub-census in 1996 and 2001 used in calculation. Rate for children <5 y: 15.6 (12.8-18.6) P L Ho, et al, The Paediatric Infection Disease Journal, Vol 25 (5) 454-455 May 2006 18.8

24. CAP in Hong Kong It was estimated that 17-28% of community acquired pneumonia among young children are due to Pneumococcus. Susan Chiu, The Education Bulletin of the Hong Kong Paediatric Society, Vol.10 no. 2, March 2003

25. Disease burden in Hong Kong Incidence of Invasive Pneumococcal Disease per 100 000 children < 5 yr* –Meningitis: 1 case –Bacteraemia: 20 cases –Pneumonia:100 cases The most common serotype: 14, 6B, 19F, 23F # (Licensed PCV7 contains: 4, 6B, 9V, 14, 18C, 19F and 23F) *Hong Kong Journal of Pediatric (New Series) 2001: 6: 127 – 132 # Dr. PL Ho et al. Vaccine 22 (2004), 3334-3339

26. Penicillin resistance in Hong Kong 13 Jacobes et al, ICAAC 1999 poster #1044

27. Vaccination against Pneumococcus Capsular antibodies directed vs specific serotypes

28. Vaccination Pneumococcal Polysaccharide vaccine (Pneumovax) –Directed against 23 capsular serotypes –Overall protective efficacy of 60- 70%

29. Recommendation for Polysaccharide Pneumococcal Vaccine Healthy elderly people (> 65 years of age), particularly those living in institutions Patients with chronic cardiopulmonary disease, DM, alcoholism, chronic liver disease, CSF leak Particular immunodeficiencies Children with high risk- sickle cell anaemia or splenectomized

30. Problems with polysaccharide vaccine in children Not effective in children less than 2 years No effect on nasal carriage No herd effect Absence of immunologic memory Antibody level to several serotypes decline to pre-vaccination values within 3-7 years corresponding to a decline of clinical protection

31. Conjugate Vaccine A new generation of pneumococcal vaccines Coating removal of the capsular polysaccharide 7 (9, 11 or 13, …) types of saccharide is separately activated and conjugated to protein carrier Conjugates are mixed to formulate vaccine

32. Conjugate Vaccine induce a T-cell dependent immune response. These vaccines are protective even in children under two years of age, and may reduce pneumococcal transmission through a herd effect

33. Prevenar (PCV7) Serotypes contained in the vaccine (4, 6B, 9V, 14, 18C, 19F, 23F) The serotypes included responsible for 85% of pneumococcal diseases and 70% of IPD in the States –65-80% in Western Industrialized countries (WHO position paper) These saccharides are coupled to a nontoxic mutant of diphtheria toxin and the protein CRM 197.

34. Coverage by PCV7 in Hong Kong Coverage by PCV7 Invasive89.7% Nasopharyngeal Carriage66.1% Invasive (resistance)*87.5% Nasopharyngeal Carriage (resistance)* 82.8% Dr. PL Ho et al. Vaccine 22 (2004), 3334-3339 * resistance to penicillin, erythromycin and cefotaxime Serotype: 14, 6B, 19F, 23F # (Licensed PCV7 contains: 4, 6B, 9V, 14, 18C, 19F and 23F)

35. Immunogenicity 212 healthy 2-month-old infants from four communities across US After 3 doses of vaccine, increasing trend of the geometric mean antibody concentrations (GMCs) were demonstrated Administration of the 4th dose demonstrating a brisk anamnestic response Rennels MB, Edwards KM, Keyserling HL, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM 197 in United States infants. Pediatrics. 1998;101:604-611

36. The Impact of Pneumococcal Conjugate Vaccine on Pneumococcal Disease

37. Direct Effect Among Children

38. Kaiser Permanente Vaccine Study: North Carolina Oct 1995 to Apr 1999 37,868 healthy infants (randomized double blinded) PCV7 (study group) or the meningococcus type C conjugate vaccine (control group) PCV7 contains serotypes responsible for 85% of pneumococcal disease in infants / children in studied population. The vaccines were administered at 2, 4, 6 and 12 to 15 months of age, along with the standard immunization schedule Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatric Infectious Disease Journal 2000; 19:187-195

39. Efficacious in Preventing IPD 97.4% efficacy fully immunized children 93.9% efficacy in intention to treat analysis 89.1% effective in reducing overall IPD regardless of serotype No increased in non-vaccine serotype IPD Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatric Infectious Disease Journal 2000; 19:187-195 PCV only cover 85% IPD serotypes ?? Cross Protection

40. Kaiser Permanente Vaccine Study – Postlicensure surveillance study Northern California Kaiser Permanente population April 1996 to March 2003 Incidence of IPD dramatically reduced in children < 2 yrs old Black S, Shinefield H, Baxter R, et al. Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J. 2004;23:485-489

41. IPD 51.5 – 98.2 IPD 81.7 – 113.8 Steven Black et al; The Pediatric Infectious Disease Journal, Vol. 23, Number 6, June 2004; 485-489

42. Pneumococcal Conjugate Vaccine Effectiveness Study USA Centers for Disease Control and Prevention Active Bacterial Core surveillance Matched Case-control study Whitney CG. Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study. The Lancet 2006; 368:1495-151502

43. Effective by serotype and Presence of Underlying Medical Conditions Serotype Vaccinated (  1 dose) vs. unvaccinated Efficacy (95% CI) AllUnderlying Medical Condition No Medical Condition All72 (65,78)77 (62, 87)71 (63, 78) Vaccine type-81 (57, 92)96 (93, 98) Vaccine related43 (6, 66)35 (-151, 83)44 (5, 67) Non-Vaccine-77 (32, 92)-36 (-122, 17) N=782 cases and N=2512 Control * Case / Control sets with chronic or Immunocompromised medical condition present Whitney CG. The Lancet 2006; 368:1495-151502

44. The 7-valent conjugate vaccine was introduced into the childhood immunization schedule on the 4th September 2006, which corresponds with week 36 above http://www.hpa.org.uk/infections/topics_az/pneumococcal/default.htm 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)

45. 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) The 7-valent conjugate vaccine was introduced into the childhood immunization schedule on the 4th September 2006, which corresponds with week 36 above http://www.hpa.org.uk/infections/topics_az/pneumococcal/default.htm

46. Efficacy Studies on Otitis Media

47. Kaiser Permanente Vaccine Study: Reduce OM visits 8.9%, OM episodes 7.0%, frequent OM 9.3%. Tubes placement 20.1% (all p<0.04), If tympanocentesis done, serotype specific efficacy 66.7% Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatric Infectious Disease Journal 2000; 19:187-195

48. Efficacy Against Otitis Media in Finland 1662 infants Overall reduction of acute OM 6% (CI –4 to 16%) Reduction in cultured confirmed pneumo OM 34% Reduction in OM from vaccine serotypes: 57% –6B, 14, 23F, (good), 19F (poor) –6A (X-react good), 19A (poor) Increase in non-vaccine serotype pneumo OM 33% Eskola, etal. Efficacy of a Pneumococcal Conjugate Vaccine against Otitis Media. NEJM 2001; 344:403-409 Not sig. 84% 25%

49. Effectiveness on Serotypes

50. Vaccine effectiveness according to serotype Effective against all 7 vaccine serotypes individually, the poorest response is to 19F Effective against vaccine-related 6A; Not effective against vaccine-related serotype 19A

51. Nasopharyngeal Carriage

52. Studies have shown that pneumococcal immunization decrease carriage of vaccine serotypes Studies also showed a decrease in carriage of PNSP types

53. Reduction of nasopharyngeal carriage of Streptococcus pneumoniae after administration of a 9-valent pneumococcal conjugate vaccine to toddlers attending day care centres 2-year FU, 264 toddlers, 9-valent PCV Rate of carriage of vaccine type lower in vaccinated children Significant protection against all vaccine serotypes except 19F Related serotypes: 6A good, 19A poor Increase in carriage of non-vaccine serotypes –11A, 33F, 35B R Dagan. The Journal of Infectious Diseases 2002; 185:927-936

54. Herd Immunity

55. When vaccinated persons in a population indirectly protect unvaccinated members by impeding the transmission of the infectious agents in the population

56. Evidence of Herd Immunity reducing disease among children Drop in vaccine type disease in children outside vaccinated age group –  50% reduction in –infants < 2 months and children 5-17 yrs Poehling K. Invasive Pneumococcal Disease Among Infants Before and After Introduction of Pneumococcal Conjugate Vaccine JAMA 2006; 295:1668-1674 Not the specific target

57. Observed reduction in vaccine type disease in children > than expected (77%) –Expected reduction = vaccine coverage (3+ doses 83%) × vaccine efficacy (92%)

58. Invasive Pneumococcal Disease, U.S., 1998-2003, by conjugate vaccination status 16. MMWR September 16, 2005 /54(36);893-897 Greater IPD reduction in unvaccinated people than in vaccinated children

59. Indirect Effect Among Adults

60. Kaiser Permanente Vaccine Study – Postlicensure surveillance study Statistically significant decrease in the risk of pneumococcal disease among all individuals older than 5 years as well as those 20-39 years of age and among those  60 years of age Black S, Shinefield H, Baxter R, et al. Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J. 2004;23:485-489

61. Effect on adults – indirect effect PCV7 reduced disease in adults by lessening transmission form children Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med. 2003;348:1737-1746 File TM, Tan JS. Pneumonia in adults, Reversing the trend. JAMA. 2005; 294: 2760-2763

62. Decline in PID - Population based study in US 1998 - 2001 Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med. 2003;348:1737-1746 Per 100 000 population1998/19992001Rate of reduction Rate of IPD (overall)24.317.3 < 2 yr1885969% p<0.001 Vaccine / vaccine related serotype 78% p<0.001 50% p<0.001 20-3911.27.632% p<0.001 40-6421.519.78% p=0.03  65 60.149.518% p<0.001 Disease Pen resistant6.34.135% p<0.001

63. Effect on antibiotic resistance

64. Kaiser Permanente Vaccine Study – Postlicensure surveillance study Compare year 1998-1999 to 2001-2002 Penicillin:28.9% to 19.5% Erythromycin:29.5% to 15.0% Tetracycline:39.3% to 13.9% p value all<0.001 Black S, Shinefield H, Baxter R, et al. Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J. 2004;23:485-489

65. Penicillin resistance PCV7 licensed

66. Invasive Disease in Children <2 years by Susceptibility to Penicillin Kyaw M et al. Effect of introduction of the Pneumococcal Conjugate Vaccine on Drug-resistant Streptococcus pneumoniae. NEJM 2006; 354: 1455-1463

67. Impact of Conjugate Vaccine on Pneumococcal Epidemiology Large decline in invasive disease rates in young children Reduction in Nasal Carriage Herd benefit in unvaccinated children and adults Indirect benefit in older children and adults Fewer antibiotic resistant infections

68. CDC’s Advisory Committee on Immunization Practices (ACIP)

69. Advisory Committee on Immunization (ACIP) Recommend use of PCV7 for: Universal vaccination of all infants  23 months of age Vaccination of all children, 24-59 months of age, with the following conditions: –Sickle cell anaemia –Splenic dysfunction –HIV / AIDS –Chronic disease –Immunocompromising condition MMWR 2000; 49(No.RR-9):1-38

70. WHO Position Statement

71. World Health Organization Has acknowledged that vaccination is the most logical and effective way to containing resistance by preventing infection in the first place –WHO, Overcoming Antimicrobial Resistance: World Health Report on Infectious Diseases 2000

72. Recommendation from the Strategic Advisory Group of Experts (SAGE) on Immunization “…… WHO considers that is should be a priority to include this vaccine in national immunization programmes, …… WHO Weekly Epidemiological Record, 23 Mar 2007 Pneumococcal Conjugate Vaccine for childhood immunization – WHO position paper. 23 March 2007, 82 nd year. No. 12, 2007, 82, 93-104. http://www.who.int/wer http://www.who.int/wer

73. Countries with Universal Vaccination with Conjugate Pneumococcal Vaccine US (Feb 2000), Canada, France (March 2002), Kuwait, Luxembourg, Netherlands,Switzerland, UK (Sept 2006), Norway, Australia, Qatar, Germany, Greece, Belgium, Italy and Mexico. Planned: New Zealand June 2008, Costa Rica, Ireland, Denmark, United Arab Emirates of Dubai and Abu Dhabi, Cyprus and Panama.

74. Safety Information In clinical trials (n=18,168), the most frequently reported adverse events included: injection site reactions fever ( 38 º C/100.4 º F) Irritability, drowsiness, restless sleep decreased appetite vomiting, diarrhea Rash …………….rate similar to other vaccines Contraindication: Hypersensitivity to any vaccine component, including diphtheria toxoid

75. Pharmacoeconomic evaluation Economic evaluation of routine Prevenar vaccination programs have been published from 11 countries: –Australia, Canada, Finland, Germany, Italy, Netherlands, Norway, Spain, Switzerland, UK and US Routine immunization with Prevenar has been shown to significantly reduce the overall cost associated with treatment of pneumococcal disease

76. Future Direction Surveillance of Hong Kong Data in order to calculate the Economic Cost Benefited from introducing the Pneumococcal Conjugate Vaccine into the Universal Immunization Program Surveillance of isolates from cases of IPD and serotype to assist in monitoring changes in serotype distribution following introduction of vaccination programs