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Pneumococcal Vaccine in Children. Pneumococcal Vaccine in Children Dr. Kwan Yat-wah Department of Paediatrics and Adolescent Medicine Princess Margaret Hospital. Streptococcus pneumoniae ( Pneumococcus). Gram Positive, -hemolytic encapsulated diplococcus

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pneumococcal vaccine in children

Pneumococcal Vaccine in Children

Pneumococcal Vaccine in Children

Dr. Kwan Yat-wah

Department of Paediatrics and Adolescent Medicine

Princess Margaret Hospital

streptococcus pneumoniae pneumococcus
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

slide3

The Pneumococcus

  • Major cause of respiratory disease and bacterial meningitis worldwide
invasive pneumococcal disease ipd
Invasive Pneumococcal Disease (IPD)
  • Case Definition:
    • Isolation of Streptococcus Pneumoniae from a normally sterile site (not including middle ear)

or

    • Demonstration of Streptococcus Pneumoniaeantigen in Cerebrospinal Fluid
slide5
Invasive pneumococcal disease (IPD)
    • Pneumonia with bloodstream infection, septicemia, meningitis
  • Localized respiratory disease
    • Middle ear infections, sinusitis, bronchitis, pneumonia
capsule polysaccharide
Capsule Polysaccharide
  • Define the virulence
  • The main target of vaccine intervention
epidemiology1
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
invasive pneumococcal disease incidence by age group england and wales 2000 pre pcv7
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)

nasopharyngeal carriage
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%
nas opharyngeal carriage of pneumococcus

60%

60

50

35%

40

29%

Carriage rate (%)

25%

30

20

6%

10

0

Preschool

Grammar school

Jr. HighSchool

Households

with children

Householdswithout children

Nasopharyngeal carriage of Pneumococcus

1 Presentation by Mark A. Fletcher, M.D., on Epidemiology of Streptococcus pneumoniae: “Pneumococcus”

pneumonia
Pneumonia
  • Largest infectious Disease Causes of Child Death Worldwide*
  • Can be bacterial / viral, but the 1st 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

burden of pneumococcal disease1
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
prevalence of ipd varies with
Prevalence of IPD varies with
  • Geographical region
  • Risk Factors:
    • Age
    • Underlying diseases
    • Ethnic Groups
incidence of ipd in children 2yrs old
Incidence of IPD in children < 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; 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

young children high risk
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

slide18
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 
invasive pneumococcal disease incidence by age group england and wales 2000 pre pcv71
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)

annual incidence of culture confirmed ipd hong kong island by age 1995 2004
Annual incidence of culture-confirmed IPD, Hong Kong Island, by age, 1995-2004.

18.8

Rate for children <5 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

disease burden in hong kong
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

slide24

Penicillin resistance in Hong Kong

13 Jacobes et al, ICAAC 1999 poster #1044

vaccination against pneumococcus
Vaccination against Pneumococcus

Capsular antibodies directed vs specific serotypes

vaccination
Vaccination
  • Pneumococcal Polysaccharide vaccine (Pneumovax)
    • Directed against 23 capsular serotypes
    • Overall protective efficacy of 60-70%
recommendation for polysaccharide pneumococcal vaccine
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
problems with polysaccharide vaccine in children
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
conjugate vaccine
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
conjugate vaccine1
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
prevenar pcv7
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.
coverage by pcv7 in hong kong
Coverage by PCV7 in Hong Kong
  • 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

immunogenicity
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. 1998;101:604-611

kaiser permanente vaccine study
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 diseasein 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
efficacious in preventing ipd
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

kaiser permanente vaccine study postlicensure surveillance study
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

slide39

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

pneumococcal conjugate vaccine effectiveness study
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
effective by serotype and presence of underlying medical conditions
Effective by serotype and Presence of Underlying Medical Conditions

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
slide42

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

slide43

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

kaiser permanente vaccine study1
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
efficacy against otitis media in finland
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; 344:403-409

25%

84%

slide48

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
slide50
Studies have shown that pneumococcal immunization decrease carriage of vaccine serotypes
  • Studies also showed a decrease in carriage of PNSP types
slide51

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
herd immunity1
Herd Immunity

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

evidence of herd immunity reducing disease among children
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

Not the specific target

Poehling K. Invasive Pneumococcal Disease Among Infants Before and After Introduction of

Pneumococcal Conjugate Vaccine

JAMA 2006; 295:1668-1674

slide55
Observed reduction in vaccine type disease in children < 5 yrs (98%) >> than expected (77%)
    • Expected reduction = vaccine coverage (3+ doses 83%) × vaccine efficacy (92%)
invasive pneumococcal disease u s 1998 2003 by conjugate vaccination status
Invasive Pneumococcal Disease, U.S., 1998-2003, by conjugate vaccination status

Greater IPD reduction in unvaccinated people than in vaccinated children

16.MMWRSeptember 16, 2005 /54(36);893-897

kaiser permanente vaccine study postlicensure surveillance study1
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

effect on adults indirect effect
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
decline in pid population based study in us 1998 2001
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

kaiser permanente vaccine study postlicensure surveillance study2
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

slide64

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

impact of conjugate vaccine on pneumococcal epidemiology
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
advisory committee on immunization acip
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

world health organization
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
recommendation from the strategic advisory group of experts sage on immunization
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

countries with universal vaccination with conjugate pneumococcal vaccine
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.
safety information
Safety Information
  • In clinical trials (n=18,168), 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
pharmacoeconomic evaluation
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
future direction
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