Download Pneumococcal Conjugate Vaccine

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
• 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
The Pneumococcus
• Major cause of respiratory disease and
bacterial meningitis worldwide
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
• Invasive pneumococcal disease (IPD)
– Pneumonia with bloodstream infection,
septicemia, meningitis
• Localized respiratory disease
– Middle ear infections, sinusitis, bronchitis,
pneumonia
Capsule Polysaccharide
• Define the virulence
• The main target of vaccine
intervention
Epidemiology
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)
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
•
•
•
•
•
•
•
Gambia:
Pakistan:
Philippines:
South Africa:
Southern Israel:
Uruguay:
Zambia:
76.1 – 85.1
51.9 – 64.4%
51 – 62%
29.4%
35% - 93%
15.2 – 42.1%
71.9%
Nasopharyngeal carriage of
Pneumococcus
60%
60
Carriage rate (%)
50
35%
40
30
25%
29%
20
10
6%
0
Preschool
1
Grammar
school
Jr. High
School
Households
Households
with children without children
Presentation by Mark A. Fletcher, M.D., on Epidemiology of Streptococcus pneumoniae: “Pneumococcus”
Burden of
Pneumococcal
Disease
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
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
• Geographical region
• Risk Factors:
– Age
– Underlying diseases
– Ethnic Groups
Incidence of IPD in children < 2yrs old
37.1-48.1
96.4
150
206.8
18.9
UK
HONG KONG
Australia
South California Argentina
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
• 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
• 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 
Risk for IPD
Age
6-11 months
< 12 months
< 23 months
Ethnicity
African American
Native American, Native
Alaskan
Australian Aborigine
Splenic Dysfunction
HIV Infection
Per 100 000
235
205
165
>400
557 – 2400
170
600-6500
587-11300
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)
Situation in Hong Kong
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
• 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
Penicillin resistance in Hong Kong
13
Jacobes et al, ICAAC 1999 poster #1044
Vaccination against
Pneumococcus
Capsular antibodies directed vs
specific serotypes
Vaccination
• Pneumococcal Polysaccharide
vaccine (Pneumovax)
– Directed against 23 capsular
serotypes
– Overall protective efficacy of 6070%
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
•
•
•
•
•
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
• 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 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)
•
•
•
•
•
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
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
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
The Impact of Pneumococcal
Conjugate Vaccine on
Pneumococcal Disease
Direct Effect Among Children
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
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
PCV only cover 85% IPD serotypes
?? Cross Protection
•
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
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
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
• 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
Serotype
Vaccinated ( 1 dose) vs. unvaccinated
Efficacy (95% CI)
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)
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
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
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
Efficacy Studies on Otitis Media
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
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)
25%
84% – 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
Effectiveness on Serotypes
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
Nasopharyngeal Carriage
• Studies have shown that pneumococcal
immunization decrease carriage of
vaccine serotypes
• Studies also showed a decrease in
carriage of PNSP types
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 Immunity
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
• 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
• 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
Greater IPD reduction
in unvaccinated people
than in vaccinated
children
16.
MMWR September 16, 2005 /54(36);893-897
Indirect Effect
Among Adults
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
• 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
Per 100 000 population
1998/1999 2001
Rate of IPD (overall)
24.3
17.3
< 2 yr
188
59
Vaccine /
vaccine related serotype
Rate of reduction
69% p<0.001
78% p<0.001
50% p<0.001
20-39
11.2
7.6
32% p<0.001
40-64
21.5
19.7
8% p=0.03
 65
60.1
49.5
18% p<0.001
Disease Pen resistant
6.3
4.1
35% p<0.001
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. 2003;348:1737-1746
Effect on antibiotic
resistance
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
Penicillin resistance
PCV7 licensed
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
• 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
CDC’s Advisory Committee on
Immunization Practices (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
WHO Position Statement
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
• “…… 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
• 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
• 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
• 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
• 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