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По материалам 4-го Европейского конгресса педиатров
L. Temimi
CNAM National University, Paris
Indirect effect and pneumococcal conjugate vaccines
A Little Theory
Infectious Disease Transmission
(^) Susceptible (^) Infected
P = primary;
S = secondary;
T = tertiary
Basic reproductive number: R0
• Mean number of secondary (S) cases contaminated by a single infected individual in a susceptible population
R0>1 : epidemics
Heffernan JM, et al. J R Soc Interface. 2005; 2: 281-293.
Ro<1 : control
More About R0
• Useful summary that depends on:
• Infectious contact duration
• Probability of transmission during contacts
• Frequency of contacts
• Measure of the intrinsic potential for an infectious agent to spread
Infection Location Ro
Measles England and Wales (1950-68) 16-18
Rubella England and Wales (1960-70) 6-7
Poliomyelitis USA (1955) 5-6
Hib Finland (1970s and 1980s) 1.04
Anderson RM, May RM. Infectious Diseases of Humans. Oxford University Press; 1991.
Auranen K, et al. Epidemiol Infect. 2004; 132: 947-957.
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What Is Indirect Protection Also Known As Herd Immunity?
Control and Immunity
• If a portion P of the population is immune, then:
• Transmission does not occur as often
• Ro is reduced to R = Ro - p x Ro
• If P > 1 - 1/Ro then R < 1: epidemic control
(^) Susceptible (^) Immune (^) Infected
P = primary;
S = secondary;
P~S Herd immunity is achieved
По материалам 4-го Европейского конгресса педиатров
Example for Measles
• Very high reproductive number: R0 = 16
• If 50% of the population is immune:
R = 50% x 16 = 8 > 1: epidemic situation
• If 99% of the population is immune:
R = 1% x 16 = 0.16 < 1: epidemic control
• Threshold value for herd immunity:
94% of immune individuals in the population
Heffernan JM, et al. J R Soc Interface. 2005; 2: 281-293.
Herd Immunity and Vaccination
If a high enough portion of the population is vaccinated, then:
• Herd immunity will be achieved
• The reduction in disease incidence will be greater than expected in the targeted subpopulation
• The disease incidence will also be reduced in nonvaccinated subpopulations
Fletcher MA, et al. Int J Clin Pract. 2006; 60: 450-456.
Herd Immunity and Streptococcus Pneumoniae
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Pneumococcal Transmission
• High frequency of asymptomatic carriage
• Up to 65% in preschool children
• Evidence for carriage transmission
• R0
• Not well defined, varies strongly with age
• Available estimates ~2.0
• Consequently, is herd immunity achievable provided > 50% of the population is immune?
Cardozo DM, et al. Braz J InfectDis. 2006; 10: 293-304.
O’Brien KL, et al. Am J Epidemiol. 2004; 159: 634-644.
Pneumococcal Vaccines
• Polysaccharide vaccines1
• Protect against invasive disease
• Do not prevent carriage and carriage transmission
• No potential for herd immunity
• Conjugate vaccines2, 3
• Effective in young children
• Protect against invasive pneumococcal disease (IPD)
• Prevent nasopharyngeal carriage
• Potential for herd immunity
1 Fedson DS, Musher DM. In: Plotkin SA, et al, eds. Vaccines. 4th ed. 2004.
2 Fletcher MA, et al. Int J Clin Pract. 2006; 60: 450-456.
3 PREVENAR*, Pneumococcal Saccharide Conjugated Vaccine, Adsorbed, Prescribing Information, Wyeth Pharmaceuticals.
* Trademark
Herd Immunity and 7-Valent Pneumococcal Conjugate Vaccine (PCV7):
What Is the Evidence?
Evidence in Children (US)
• In the US between 2000 and 2004:
• Expected reduction in the incidence
of vaccine-serotype IPD in children < 5 yrs:
• 77% = coverage (3 + doses 83%) x efficacy (92%)
• Observed reduction in children < 5 yrs:
• 94% >> expected
• ~50% reduction in IPD among infants < 2 months and children 5-17 yrs (outside targeted age group)
Poehling K, et al. JAMA. 2006; 295: 1668-1674.
CDC. Morb Mortal Wkly Rep. 2005; 54: 893-897.
Evidence in Children (US)
IPD Incidence in the US in Children < 5 Years Old Vaccine and nonvaccine serotype IPD
<1 y
1 У
2-4 y
ABCs
surveillance data, US Centers for Disease Control and Prevention
CDC. ABCs surveillance data. http://www.cdc.gov/ncidod/dbmd/ abcs/survreports.htm. Accessed August 13, 2008.
Evidence in Adults (US)
• In the US between 2000 and 2003:
• Significant reduction in vaccine-type IPD incidence in all age groups (5-17, 18-39, 40-64, > 65 yrs)
• 29% reduction in total IPD (vaccine and nonvaccine
serotypes) incidence among persons aged > 5 yrs
• Not explainable by polysaccharide vaccination CDC. Morb Mortal Wkly Rep. 2005; 54: 893-897.
Evidence in Adults (US) (cont’d)
IPD Incidence in the US in > 5 Years Old Vaccine and nonvaccine serotype IPD
70 -i 6050403020100
.Vaccine introduction
35% reduction
ABCs
surveillance data, US Centers for Disease Control and Prevention
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 -> 65 y -4 50-64 y .*-35-49y 18-34 y -#-5-17y
CDC. ABCs surveillance data. http://www.cdc.gov/ncidod/dbmd/ abcs/survreports.htm. Accessed August 13, 2008.
Evidence in Adults (Canada)
Adults - Reductions in IPD Due to Vaccine Serotypes
62.7% Reduction
p = 0,007
1998-2001 rr 2004r
-3 65 years of age Canada (Calgary)
□ Pre-licensure □ Post-licensure Kellner JD, et al. CMAJ. 2005; 173: 1149-1151.
PCV7—significant reduction of invasive pneumococcal disease (IPD) in unvaccinated populations after routine childhood immunization programs
The Calgary Area Streptococcus pneumoniae Epidemiology Research (CASPER) team conducts prospective population-based surveillance of all cases of invasive S. pneumoniae infection occurring in the Calgary Health Region, whose population now exceeds 1 million.
Data collected from 1998 to 2004. When compared with the combined rate between 1998 and 2001, the rate in 2004 decreased by 62.7% to 8.5 (95% CI 3.7-16.7) for PCV7 serotypes (p = 0.007)
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Impact of Herd Immunity on PCV7 (Cost-)effectiveness
Direct vs Indirect Effects
Estimated number of cases of vaccine-type (VT) IPD prevented by direct* and indirect^ effects of PCV7 -Active Bacterial Core surveillance, United States, 2003
25.000
20.000
® 15,000 £
£
z 10,000 5,000 0
CDC. Morb Mortal Wkly Rep. 2005; 54: 893-897.
20,459
9,140
n
Greater IPD Reduction in Unvaccinated Adults than in Vaccinated Children
ABCs surveillance data, US Centers for Disease Control and Prevention
* Direct VT IPD cases prevented in 2003 = 1998 to 1999 average number of VT IPD cases in children aged < 5 years x 2003 PCV7 coverage with 3 doses (68.1%) x PCV7 effectiveness for VT IPD (93.9%)
t Indirect VT IPD cases prevented in 2003 =
(1998 to 1999 average number of VT IPD cases across all age groups - 2003 number of IPD cases across all age groups) - 2003 direct VT IPD cases prevented. Calculation of indirect cases prevented does not account for replacement disease
Effect
nEflMATPMHECKAfl ^APMAKOflOrMfl /2009/ TOIVI 6/ № 5
По материалам 4-го Европейского конгресса педиатров
Estimated Cost-effectiveness Analysis (USA)
Cost per Life-year Saved by PCV7 in the First 5 Years
120 000 110 000
— 100 000-о
% 80 000 -
~ 60 000 -
° 40 000 -
20 000 8000
0
Before With herd
incorporating effects
any herd (based
effect on ABCs data)
18 500
Assume IPD herd effect is half
Ray GT, et al. PediatrInfectDis J. 2006; 25: 494-501.
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Estimated Cost-effectiveness: With and Without Indirect (Herd) Effects
t 100
o 50
$112
£59
а Ш:
€101
€58 €59
lb
USA (S) UK 1 (P) UK 2 (P) Germany (P) Norway (S) Netherlands (S)
Without Indirect Effects
□ With Indirect Effects
P: Payer Perspective S: Societal Perspective
1 Ray GT, et al. Pediatr Infect Dis J. 2006; 25: 494-501.
2 Melegaro A, Edmunds WJ. Vaccine. 2004; 22: 4203-4214.
3 McIntosh ED, et al. Vaccine.2005; 23: 1739-1745.
4 Hubben GAA, et al. Vaccine. 2007; 25: 3669-3678.
5 Wisloff T, et al. Vaccine. 2006; 24: 5690-5699.
6 Lloyd A, et al. Eur J Health Econ. 2007; 9: 7-15.
о 0
Another Possible Indirect Effect: Serotype Replacement
What Is Serotype Replacement?
• > 90 pneumococcal serotypes1
• PCV7 covers 7 serotypes2
• Which cause at least 80% of IPD cases in children
• Evidence in vaccinated populations3-5
• Increase in carriage of non-vaccine serotypes
• Increase in non-vaccine IPD incidence
• Evidence in non-vaccinated subpopulations (older children and adults)5, 6
• Also observed in countries without PCV7 (Israel, Korea)
1 Park IH, et al. J Clin Microbiol. 2007; 45: 1225-1233.
2 Hausdorff WP, et al. Clin Infect Dis. 2000; 30: 100-121.
3 Pelton SI, et al. Pediatr Infect Dis J. 2004; 23: 1015-1022.
4 CDC. Morb Mortal Wkly Rep. 2008; 57: 144-148.
5 Hicks LA, et al. J Infect Dis. 2007; 196: 1346-1354.
6 Moore MR, et al. J Infect Dis. 2008; 197: 1016-1027.
Rates of Invasive Pneumococcal Disease (IPD) in Children, USA (1998 to 2004)
PCV7y6er0types
erotypes
1998 1999 2000 2001 2002 2003 2004
Rates of invasive pneumococcal disease among children aged <5 years by serotype and year.
The 7-valent pneumococcal conjugate vaccine (PCV7) includes serotypes 4, 6B, 9V, 14, 18C, 19F and 23F.
PCV7 introduced
Hicks LA, et al. J Infect Dis. 2007; 196: 1346-1354.
Baseline
Expansion of Serotype 19A
60
e40
7F 12F 15 \19A / 22F 33F 38 Other
Serotype □ 1998-1999 □ 2004
c 10 -O
to 5 -
1991-1994 1995-1999 2000-2006
USA, changes over 5 years
Hicks LA, et al. JInfectDis. 2007; 196: 1346-1354.
Korea, changes over 5 years
Choi et al., Emerg Infect Dis. 2008; 14: 275-281
25
80
23
20
0
0
0
PCV7 3
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Cost-effectiveness Analysis
si 100 000 -3 80 000 -ted60 000
Without any indirect With herd With herd immunity and effect immunity serotype replacement
0
Melegaro A, Edmunds WJ. Vaccine. 2004; 22: 4203-4214.
Indication for PCV7
• PCV7 is indicated for Active immunization against disease caused by Streptococcus pneumoniae serotypes 4, 6B, 9V,14,18C,19F and 23F (including sepsis, meningitis, pneumonia, bacteraemia and acute otitis media) in infants and children from 2 months up to 5 years of age.
Please see Product Information.
nEflMATPMHECKAfl ^APMAKOflOrMfl /2009/ TOM 6/ № 5
По материалам 4-го Европейского конгресса педиатров
Important Safety Information for PCV7
• In clinical studies (n = 18,168), the most frequently reported adverse events included injection site reactions, fever
(^ 38°C/100.4°F), irritability, drowsiness, restless sleep, decreased appetite, vomiting, diarrhea, and rash.
• Risks are associated with all vaccines, including PCV7. Hypersensitivity to any vaccine component, including diphtheria toxoid, is a contraindication to its use.
PCV7 does not provide 100% protection against vaccine serotypes or protect against nonvaccine serotypes.
The decision to administer PCV7 should be based on its efficacy in preventing invasive pneumococcal disease (IPD).
• The minimum serum antibody concentration necessary for protection against invasive pneumococcal disease has not been determined for any serotype.
Please see Product Information.
Important Safety Information for PCV7
• The frequency of pneumococcal serotypes and serogroups can vary from country to country, which could influence the effectiveness of the vaccine in any given country.
• PCV7 is not indicated for use in adults or in infants younger than 2 months of age.
• The CDC Surveillance System has reported an increased incidence of IPD due to nonvaccine serotypes in children < 5 and in adults 40 years of age. It is unknown whether these effects would be observed in other populations.
• Because both otitis media and pneumonia may be caused by many organisms other than serotypes of S. pneumoniae represented in the vaccine, protection against all clinical otitis media or pneumonia is expected to be lower than
for invasive disease.
Please see Product Information.
Conclusions
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Indirect Effects of PCV7
• Strong evidence for herd immunity with PCV7
• When incorporated into national immunization programmes
• Herd immunity should begin to be achieved when approximately more than half of the birth cohort is vaccinated
• Due to the indirect (herd) effect, the fall in IPD incidence in the US has been more than double that anticipated by the direct effect only
• Vaccine cost-effectiveness may also be improved
• The possibility for serotype replacement should still be taken into account
• And should be tracked accordingly by ongoing surveillance
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