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)

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

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%

Nasopharyngeal carriage of Pneumococcus

10

20

30

40

50

Preschool Grammar school

Jr. HighSchool

Car

riag

e ra

te (

%)

6060%

35%

25%

0

Households with children

Householdswithout children

29%

6%

1 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

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

96.4150

South California

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 ho

me had a 36-fold in risk of IPD– attended family daycare had a 4.4-fold

Risk for IPDAge Per 100 000

6-11 months 235

< 12 months 205

< 23 months 165

Ethnicity

African American >400

Native American, Native Alaskan

557 – 2400

Australian Aborigine 170

Splenic Dysfunction 600-6500

HIV Infection 587-11300

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

Situation in Hong Kong

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

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 60-70%

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%

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)

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

• 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

• 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

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)

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

• 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%

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

Poehling K. Invasive Pneumococcal Disease Among Infants Before and After Introduction of Pneumococcal Conjugate VaccineJAMA 2006; 295:1668-1674

Not the specific target

• 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

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

Greater IPD reduction in unvaccinated people than in vaccinated children

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

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 population 1998/1999 2001 Rate of reduction

Rate of IPD (overall) 24.3 17.3

< 2 yr 188 59 69% p<0.001

Vaccine /

vaccine related serotype

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

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 mont

hs of age• Vaccination of all children, 24-59 months of a

ge, 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