Pneumococcal Vaccine in Children

1
Pneumococcal Vaccine in Children

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

2
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 451225-1233
3
The Pneumococcus

• Major cause of respiratory disease and bacterial
  meningitis worldwide

4
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

5

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

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Capsule Polysaccharide

• Define the virulence
• The main target of vaccine intervention

7

• Epidemiology

8
Epidemiology

• 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

9
Invasive Pneumococcal Disease Incidence by Age
Group England and Wales 2000 (pre-PCV7)
Germany 8.9 per 100,000 children Switzerland
7.6 per 100,000 children England and Wales 14.5
per 100,000 children
Health Protection Agency Communicable Disease
Surveillance Centre. CDR Weekly 2003 12(21)
10
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

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Nasopharyngeal carriage of Pneumococcus
1 Presentation by Mark A. Fletcher, M.D., on
Epidemiology of Streptococcus pneumoniae
Pneumococcus
12

• Burden of Pneumococcal Disease

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Pneumonia

• Largest infectious Disease Causes of Child Death
  Worldwide
• Can be bacterial / viral, but the 1st cause if
  Streptococcus Pneumoniae
• Responsible for gt1 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

14
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

15
Prevalence of IPD varies with

• Geographical region
• Risk Factors
• Age
• Underlying diseases
• Ethnic Groups

16
Incidence of IPD in children lt 2yrs old
206.8
150
37.1-48.1
96.4
18.9
UK
Australia
HONG KONG
Argentina
South California
Robinson KA JAMA 2001 Davidson M JID 1994
ODempsey 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
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Young Children High Risk

• Risk factors for IPD are
• Children lt 2 years of age
• Underlying disease
• Children who attend daycare in previous 3 months
• Risk factors for penicillin-resistant IPD
• Children exposed to gt 1 course of antibiotics
• Children with history of gt 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

18

• A Finnish study (children lt 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 ?

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Risk for IPD
Age Per 100 000
6-11 months 235
lt 12 months 205
lt 23 months 165
Ethnicity
African American gt400
Native American, Native Alaskan 557 2400
Australian Aborigine 170
Splenic Dysfunction 600-6500
HIV Infection 587-11300
20
Invasive Pneumococcal Disease Incidence by Age
Group England and Wales 2000 (pre-PCV7)
Germany 8.9 per 100,000 children Switzerland
7.6 per 100,000 children England and Wales 14.5
per 100,000 children
Health Protection Agency Communicable Disease
Surveillance Centre. CDR Weekly 2003 12(21)
21

• Situation in Hong Kong

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Annual incidence of culture-confirmed IPD, Hong
Kong Island, by age, 1995-2004.
18.8
Rate for children lt5 y 15.6 (12.8-18.6)
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.
P L Ho, et al, The Paediatric Infection Disease
Journal, Vol 25 (5) 454-455 May 2006
23
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
  

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Disease burden in Hong Kong

• Incidence of Invasive Pneumococcal Disease per
  100 000 children lt 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
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Penicillin resistance in Hong Kong
13 Jacobes et al, ICAAC 1999 poster 1044
26

• Vaccination against Pneumococcus

Capsular antibodies directed vs specific serotypes
27
Vaccination

• Pneumococcal Polysaccharide vaccine (Pneumovax)
• Directed against 23 capsular serotypes
• Overall protective efficacy of 60-70

28
Recommendation for Polysaccharide Pneumococcal
Vaccine

• Healthy elderly people (gt 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

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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

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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

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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

32
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 CRM197.

33
Coverage by PCV7 in Hong Kong
Coverage by PCV7
Invasive 89.7
Nasopharyngeal Carriage 66.1
Invasive (resistance) 87.5
Nasopharyngeal Carriage (resistance) 82.8

• Serotype 14, 6B, 19F, 23F
• (Licensed PCV7 contains
• 4, 6B, 9V, 14, 18C, 19F and 23F)

Dr. PL Ho et al. Vaccine 22 (2004), 3334-3339
resistance to penicillin, erythromycin and
cefotaxime
34
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 CRM197 in
  United States infants. Pediatrics.
  1998101604-611

35

• The Impact of Pneumococcal Conjugate Vaccine on
  Pneumococcal Disease

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Direct Effect Among Children
37
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 19187-195

38
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 19187-195

PCV only cover 85 IPD serotypes ?? Cross
Protection
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Kaiser Permanente Vaccine Study Postlicensure
surveillance study

• Northern California Kaiser Permanente population
• April 1996 to March 2003
• Incidence of IPD dramatically reduced in children
  lt 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. 200423485-489

40
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
41
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 3681495-151502

42
Effective by serotype and Presence of Underlying
Medical Conditions
Serotype Vaccinated (? 1 dose) vs. unvaccinated Efficacy (95 CI) Vaccinated (? 1 dose) vs. unvaccinated Efficacy (95 CI) Vaccinated (? 1 dose) vs. unvaccinated Efficacy (95 CI)
Serotype All Underlying Medical Condition No Medical Condition
All 72 (65,78) 77 (62, 87) 71 (63, 78)
Vaccine type - 81 (57, 92) 96 (93, 98)
Vaccine related 43 (6, 66) 35 (-151, 83) 44 (5, 67)
Non-Vaccine - 77 (32, 92) -36 (-122, 17)
N782 cases and N2512 Control Case / Control
sets with chronic or Immunocompromised medical
condition present
Whitney CG. The Lancet 2006 3681495-151502
43
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)
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
44
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
45
Efficacy Studies on Otitis Media
46
Kaiser Permanente Vaccine Study

• Reduce OM visits 8.9, OM episodes 7.0, frequent
  OM 9.3. Tubes placement 20.1 (all plt0.04),
• 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 19187-195

47
Efficacy Against Otitis Media in Finland
Not sig.

• 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 344403-409

25
84
48

• Effectiveness on Serotypes

49
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

50
Nasopharyngeal Carriage
51

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

52
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 185927-936

53

• Herd Immunity

54
Herd Immunity

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

55
Evidence of Herd Immunity reducing disease among
children

• Drop in vaccine type disease in children outside
  vaccinated age group
• ? 50 reduction in
• infants lt 2 months and children 5-17 yrs

Not the specific target
Poehling K. Invasive Pneumococcal Disease Among
Infants Before and After Introduction of
Pneumococcal Conjugate Vaccine JAMA 2006
2951668-1674
56

• Observed reduction in vaccine type disease in
  children lt 5 yrs (98) gtgt than expected (77)
• Expected reduction vaccine coverage (3 doses
  83) vaccine efficacy (92)

57
Invasive Pneumococcal Disease, U.S., 1998-2003,
by conjugate vaccination status
Greater IPD reduction in unvaccinated people than
in vaccinated children
16. MMWR September 16, 2005 /54(36)893-897
58
Indirect Effect Among Adults
59
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. 200423485-489

60
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. 20033481737-1746
• File TM, Tan JS. Pneumonia in adults, Reversing
  the trend. JAMA. 2005 294 2760-2763

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Decline in PID - Population based study in US
1998 - 2001
Per 100 000 population 1998/1999 2001 Rate of reduction
Rate of IPD (overall) 24.3 17.3
lt 2 yr 188 59 69 plt0.001
Vaccine / vaccine related serotype 78 plt0.001 50 plt0.001
20-39 11.2 7.6 32 plt0.001
40-64 21.5 19.7 8 p0.03
? 65 60.1 49.5 18 plt0.001
Disease Pen resistant 6.3 4.1 35 plt0.001

• 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. 20033481737-1746

62

• Effect on antibiotic resistance

63
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 alllt0.001
• 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. 200423485-489

64
Penicillin resistance
PCV7 licensed
65
Invasive Disease in Children lt2 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
66
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

67

• CDCs Advisory Committee on Immunization
  Practices (ACIP)

68
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
69

• WHO Position Statement

70
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

71
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, 82nd year. No. 12, 2007, 82,
  93-104. http//www.who.int/wer

72
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.

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Safety Information

• In clinical trials (n18,168), the most
  frequently reported adverse events included
• injection site reactions
• fever ( 38ºC/100.4ºF)
• Irritability, drowsiness, restless sleep
• decreased appetite
• vomiting, diarrhea
• Rash
• .rate similar to other vaccines
• Contraindication Hypersensitivity to any vaccine
  component, including diphtheria toxoid

74
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

75
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