1. National Immunization Conference
Invasive Pneumococcal Disease Trends in the United States: an Update from Active Bacterial Core Surveillance
Good afternoon
I will present Active Bacterial Core surveillance data on trends in invasive pneumococcal disease
National Immunization Conference
Match 5-8, 2007
Tamara Pilishvili, MPH

2. Background
Pneumococcus is a major pathogen causing invasive and non-invasive infections worldwide
An estimated 65,000 cases of invasive pneumococcal disease (IPD) occurred annually in the U.S. in
25% of all IPD among children <5 years old
80% of IPD among children <5 years old caused by seven pneumococcal serotypes
Streptococcus pneumoniae or pneumococcus is a major pathogen causing invasive and non-invasive infections worldwide
According to estimates, around 65,000 cases of invasive pneumococcal disease (or IPD) occurred annually in the US
25% of these were among children less than 5 years if age
And 80% of IPD in this age group were caused by seven pneumococcal serotypes

3. Background
A seven-valent pneumococcal conjugate vaccine (PCV7) has been used as a part of routine immunization schedule among infants and young children in the U.S. since late 2000
ACIP recommends a 4-dose schedule (2, 4, 6 months of age; booster dose at months of age)
In late 2000, a seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the US as part of routine immunization schedule to prevent pneumococcal disease among young children and infants
The vaccine is recommended on a 4 dose schedule: at 2, 4, 6 months of age with a booster dose given at months of age

4. Intermittent shortages
PCV7 coverage among children aged months, United States,
Сoverage with >3 doses PCV7
83%
PCV7 introduction 7%
The slide here presents National Immunization Survey estimates of PCV7 coverage for 3 or more doses among children months of age
Shortly after vaccine was introduced, multiple shortages of the vaccine were reported resulting in initially low coverage of 7% in The coverage increased in subsequent years, and in % coverage was reported
Intermittent shortages
(8/01-9/04)
CDC National Immunization Survey, 2005

5. Background Introduction of PCV7 in the U.S. has led to
a large decline in invasive pneumococcal disease (IPD) among <5 year olds
herd effect in children and adults
some increase in IPD due to serotypes not included in PCV7 (replacement disease)
increases in non-PCV7-type IPD small compared to observed declines
In spite of these shortages and initially low coverage, shortly after vaccine introduced
- large declines in IPD among children in the vaccine target age group were reported
- in addition, declines in disease among unvaccinated children and adults were noted (so called vaccine herd effect)
- some increases in IPD caused by serotypes not included in the vaccine were noted (so called replacement disease
- these increases were small compared to large declines in vaccine type disease

6. 9.1% of U.S. population of >298 million
ABCs methods
Case definition: S. pneumoniae isolated from normally sterile site in a surveillance area resident
Active contact with clinical laboratories to identify cases
Audits ensure completeness of reporting
Chart review for clinical information
Isolates serotyped at reference laboratories (CDC and MDH)
9.1% of U.S. population of >298 million
We identify cases of IPD through Active Bacterial Core surveillance (ABCs), an active population- and laboratory-based system currently ongoing at 9 sites
The total population under surveillance was over 18 million according to 2005 post-censal population estimates.  
In ABCs, we define cases of IPD as isolation of Streptococcus pneumoniae from normally sterile sites such as blood, cerebrospinal fluid, or pleural fluid.
Cases are identified through active contact with all clinical laboratories in a surveillance area
Audits ensure completeness of reporting
Charts are reviewed to attain clinical information
Isolates are serotyped at the reference laboratories
Total population
~18 million

7. Methods
IPD incidence
Numerators: cases from ABCs sites under continuous surveillance
Denominators: population estimates from the U.S. Census Bureau ( ) or NCHS post-censal ( )
Compared incidence rates of IPD in 2005 to baseline average rates
Estimated national IPD cases
based on age and race distribution of the US population
We calculated annual incidence rates of IPD (cases per 100,000 population)
- using ABCs cases from sites under continuous surveillance during the period of 1998 through 2005 as numerators
- and US Census Bureau population estimates as denominators
Percent changes in rates of disease were calculated comparing year 2005 incidence rates with pre-vaccine baseline in
To estimate the annual number of cases of IPD in the U.S., we applied race- and age-specific incidence rates derived from ABCs areas to the race and age distribution of the U.S population.  

8. Vaccine direct effects: Rates of invasive disease among children aged <5 years, 1998/99-2005
PCV7 intro-duction
All Serotypes: -76% (-79,-73)
PCV7 Types: -98% (-99,-97)
22-25 cases per 100,000
The graph on this slide presents changes in overall IPD and IPD caused by seven vaccine serotypes among children <5 years of age. Compared to baseline, rates of overall IPD were 76% lower and rates of IPD caused by PCV7-types were 98% lower in 2005 among children in this age group
In 2002 through 2005, the incidence of overall IPD among children <5 leveled off at cases per 100,000, while the incidence of PCV7-type IPD continued to decrease to 2 cases per 100,000
2 cases per 100,000
CDC, unpublished data

9. Indirect effects: Rates of invasive disease among adults aged >18 years, 1998/ All serotypes
>80: -40% (-47,-32)
65-79: -32% (-39,-25)
50-64: -14% (-22,-5)
18-49: -34% (-39,-29)
We observed dramatic indirect effects, or herd immunity effect, of PCV7 use in children on disease rates among adults of all age groups. The reduction in overall disease rates among adults ranged from 14% among 50 to 64 year olds to 40% among those 80 years old or older.
CDC, Unpublished, 2006

10. Indirect effects: Rates of invasive disease among adults aged >18 years, 1998/ PCV7 serotypes
>80: -84% (-88,-79)
65-79: -81% (-85,-76)
50-64: -75% (-79,-69)
18-49: -84% (-84,-76)
And these reductions were due to decreases in disease rates caused by seven pediatric vaccine serotypes. The graph here shows decreases in the rates of PCV7type disease among adults. The greatest reductions in PCV7-type IPD between the baseline period and 2005 occurred among elderly, those with the highest baseline rates
CDC, Unpublished, 2006

11. Rates of invasive disease among adults aged >18 years, 1998/99-2005 PPV16* serotypes
>80: (9,59)
65-79: 34 (14,56)
50-64: 43 (23,65)
18-49: (14,45)
To examine whether changes in IPD among adults may be related to the use of 23-valent polysaccharide vaccine PPV23 recommended for use in adults, we examined changes in disease rates caused by serotypes included only in PPV23 but not in PCV7.
We did not observe any reductions in disease due to these serotypes, but rather increases in rates of disease caused by these serotypes for all age groups were observed
The key message of this slide is that the overall changes in IPD in adults do not appear to be related to PPV23 use
Key message: Overall declines in IPD do not appear to be related to PPV23.
CDC, Unpublished, 2006
*Includes types included in PPV23 but NOT PCV7

12. Serotype replacement
Serotype replacement, or increases in disease caused by serotypes not included in the vaccine following the vaccine introduction has been noted following the vaccine introduction

13. Rates of invasive disease among all ages, 1998/99-2005 Non-PCV7 types*
<5: +74% (39,118) : -17% (-43,21)
18-49: % (3,31) : +45% (26,67)
65-79: +25% (7,46) >80: +21% (1,45)
In 2005 compared to baseline, the incidence rates of IPD caused by non-PCV7 types increased significantly among children and adults of all age groups, with the largest percent increase of 74% observed among children <5 years of age.
*Excludes all PCV7-type & PCV7-related serotypes.
CDC, Unpublished, 2006

14. Rates of invasive disease among all ages, 1998/99-2005 Serotype 19A
>80: +145% (61,272)
65-79: +179% (111,268)
50-64: +285% (159,473)
18-49: +235% (147,354)
5-17: % (85,639)
<5: +255% (160,385)
The most worrisome are increases in the incidence of disease caused by serotype 19A. The incidence of IPD caused by serotype 19A increased significantly among all age groups. Although percent changes were large, (please note the scale change): the absolute rate increases were small compared to changes in overall disease
The absolute rate increases in 2005 compared to baseline were the largest among children < 5 years and very elderly (6.3 and 6.4 cases per 100,000, respectively)
CDC, Unpublished, 2006

15. Serotype distribution among children <5 years 2004/2005 vs
1998/1999
2004/2005
The bar graph here demonstrates changes in the distribution of PCV7 and non-pcv7 serotypes before and after the vaccine introduction. Prior to PCV7 introduction, 7 vaccine serotypes accounted for more than 80% of IPD among children <5 years of age. In , PCV7 types accounted for only 10% of IPD in this age group, and serotype 19A accounted for 36% of all IPD cases (compared to only 2.5% in )
19A=2.5% of all strains
19A=36% of all strains
CDC, Unpublished data

16. Serotype distribution among adults 65-79 years 2004/2005 vs. 1998/1999
Similar shift in the distribution of serotypes is seen among adults. Among adults year of age before the 7-valent vaccine was introduced, PCV7 types accounted for 55% of IPD cases, and in this number is reduced to 19% of IPD. Serotype 19A accounted for 13.5% of IPD cases in this age group, compared to 3.7% in
19A=3.7% of all strains
19A=13.5% of all strains
CDC, Unpublished data

17. Antibiotic resistance
An additional benefit of the conjugate vaccine introduction has been a decrease in antibiotic resistant infections.

18. Rates of antibiotic nonsusceptible invasive disease among children aged <5 years, 1998/99-2005
The vaccine introduction has led to dramatic declines in the incidence of IPD non-susceptible to penicillin, erythromycin and cefotaxime among children <5 years of age
The conjugate vaccine does not target antibiotic-resistant disease specifically. So, why did we seen this effect?
CDC, unpublished data

19. Penicillin nonsusceptibility among serotypes causing invasive pneumococcal disease among children <5 years Percent of all invasive strains, 1998/1999
PCV7 types
non-PCV7 types
83% of all PEN-NS strains
The slide here shows the distribution of pneumococcal serotypes by susceptibility to penicillin among children <5 years of age before the vaccine introduction. Penicillin non-susceptible isolates are presented with yellow portions of bars.
7 vaccine serotypes accounted for 83% of all Pen NS isolates in
CDC, Unpublished, 2005

20. 19A=73% of all PEN-NS strains
Penicillin nonsusceptibility among serotypes causing invasive pneumococcal disease among children <5 years Percent of all invasive strains, 2004/2005
PCV7 types
non-PCV7 types
7.5% of all PEN-NS strains
19A=73% of all PEN-NS strains
Because of this association between serotype and resistance, the introduction of the conjugate vaccine had a substantial effect on resistant pneumococcal disease In , PCV7 types accounted for only 7.5% of PEN NS isolates among children <5 years of age. Serotype 19A isolates alone accounted for 73% of PEN NS isolates
CDC, Unpublished, 2005

21. Rates of antibiotic nonsusceptible invasive disease among adults aged 65-79 years, 1998/99-2005
Among adults, we saw decreases in rates of IPD non-susceptible to Pen, Ery, and cefotaxime. In , the rates have increased slightly
CDC, unpublished data

22. Penicillin nonsusceptibility among serotypes causing invasive pneumococcal disease among adults years Percent of all invasive strains, 1998/1999
PCV7 types
non-PCV7 types
74% of all PEN-NS strains
If we look at the distribution of pneumococcal serotypes by susceptibility to penicillin among adults in this age group before the vaccine introduction, 7 vaccine serotype accounted for 74% of PEN NS isolates.
CDC, Unpublished, 2005

23. 19A=35% of all PEN-NS strains
Penicillin nonsusceptibility among serotypes causing invasive pneumococcal disease among adults years Percent of all invasive strains, 2004/2005
PCV7 types
non-PCV7 types
19A=35% of all PEN-NS strains
28% of all PEN-NS strains
After vaccine introduction, decrease in rates of disease caused of 7 vaccine serotypes, resulted in a decrease of PEN NS infections. In , seven vaccine serotypes account for 28% of PEN NS isolates. With the increases observed in non-vaccine serotype disease, a larger proportion of non-vaccine serotypes account for PEN non-susceptible infections. Serotype 19A is responsible for 35% of all PEN NS IPD in in this age group.
CDC, Unpublished, 2005

24. Overall Vaccine Impact
So, what was the overall impact of the 7-valent conjugate vaccine introduction in the US

25. Direct vs. indirect effects on IPD among children aged <5 years in the U.S.
This graph presents annual estimates of vaccine direct and indirect effects in the US population of children < 5 years of age. Vaccine direct effects were calculated using estimates of vaccine coverage from NIS, and known vaccine efficacy. We estimate that the vaccine introduction directly prevented 36,000 cases form 2001 through 2005 (presented here in red bars. The vaccine introduction prevented an estimated 28,000 cases <5 years of age through herd immunity (presented in blue bars). Even if we take into account more than 2000 additional cases caused by non vaccine serotypes (presented in orange bars), the net effect of the vaccine (shown here with a green line) is still positive
Overall more than 62,000 cases < 5 years of age have been prevented in the US through vaccine direct and indirect effects.
* PCV7-related, non-PCV7 types, and serotype 19A
CDC, Unpublished, 2006

26. Indirect effect among adults >50 years
50-64 years: cases prevented
65+ years: cases prevented
Total: cases prevented
The impact on disease among adults >50 years is presented on this slide
From 2001 through 2005, an estimated 2900 cases of invasive pneumococcal disease were prevented among adults years of age, and more than cases were prevented among adults 65 years of age and older; with the total of over 30,000 cases prevented.

27. Summary Increasing incidence of IPD caused by non-PCV7 types
Large direct & indirect effects of PCV7 on invasive pneumococcal disease still evident
Increasing incidence of IPD caused by non-PCV7 types
Serotype 19A is the most common replacement serotype
Other replacement serotypes (15, 22F, 33F, 7F, 3, 38, 12F)
Increasing prevalence of antibiotic resistance among non-PCV7 strains (especially 19A)
Reductions in PCV7-type IPD continue to far outweigh increases in IPD caused by other serotypes.
In summary, large direct and indirect effects of the vaccine introduction on invasive disease in the US are still evident after 5 years of vaccine use
An increase in the incidence of disease caused by serotypes not included in the vaccine formulation is evident,
With serotype 19A becoming the most common replacement serotype
There is an increase noted in other non-vaccine serotypes and increase in prevalence of antibiotic resistance among non-PCV7 serotypes (especially type 19A)
Reductions in vaccine serotype disease continue to far outweigh replacement disease

28. Conclusions PCV7 is an effective IPD prevention measure
Higher valency vaccines are needed for children to prevent IPD caused by replacement serotypes: serotype 19A should be included in the next generation conjugate vaccines
Ongoing surveillance is critical to monitor the emergence of replacement serotypes
Large burden of disease in adults, especially in elderly: opportunities for prevention using conjugate vaccines in adults
Pneumococcal conjugate vaccine is an effective IPD prevention measure
Higher valency vaccines are needed for children to prevent IPD caused by replacement serotypes
Despite large reductions in disease among adults, rates of IPD in 2005 remain high, especially among older adults; development of conjugate vaccines for adults should be a high priority for public health
Ongoing surveillance is crucial to monitor the emergence of replacement serotypes

29. Future Directions
Higher valency conjugate vaccines for children and adults are in various stages of development
Improving coverage of PPV23 among adults is important
Common protein vaccines may provide protection against all pneumococcal serotypes
New higher valency conjugate vaccines for children and adults are in various stages of development and should prevent IPD caused by a greater variety of pneumococcal serotypes.
Improving coverage with the existing polysaccharide vaccine for adults is also important, as low coverage with PPV23 continues despite the long-standing availability of that vaccine.
Finally, common protein vaccines that might provide protection against all pneumococcal serotypes could also have a major impact on the burden of IPD

30. Acknowledgements ABCs sites Monica Farley Sue Petit Wendy Baughman
David Stephens
Nana Bennett
Shelley Zansky
Zach Frazer
Jim Hadler
Lee Harrison
Lauri Thompson Sanza
Karen Stefonek
Paul Cieslak
Art Reingold
Pam Daily
Ruth Lynfield
Catherine Lexau
John Besser
Sue Petit
Allen Craig
Bill Schaffner
Brenda Barnes
Steve Burnite
Ken Gershman
B. Juni
UTHSC San Antonio
Jim Jorgensen
Lettie McElmeel
Sharon Crawford
CDC/Respiratory diseases branch
Cynthia Whitney
Matt Moore
Chris Van Beneden
Tami Skoff
Bernard Beall
Genny Gallagher
Anne Schuchat
Elizabeth Zell
Carolyn Wright
Emily Weston
Dee Jackson
I would like to thank the following people for their contribution to Active Bacterial Core Surveillance
Thank you for your attention

31. Changes in disease syndromes among adults with IPD, 1998/99 vs. 2004/05
Cases/100,000
18-64 years
Bacteremia
4.11
1.76
Pneumonia
10.52
8.16
Meningitis
0.85
0.77
>65 years
14.35
6.27
42.84
30.78
1.90
0.87

32. Changes in prevalence of underlying illnesses among adults with IPD, 1998/99 vs. 2004/05
% IPD cases
18-64 years
Overall
57.37
65.12
Bacteremia
54.46
63.09
Pneumonia
58.83
67.24
Meningitis
50.36
47.89
>65 years
64.49
74.60
50.94
68.47
68.54
76.75
60.00
51.61

33. Effectiveness of different infant schedules
Schedule, by months of age
at time of doses
Effectiveness, %
95% confidence interval
1 dose ≤7 months 73
43, 87
2 doses ≤7 months 96
88, 99
3 doses ≤7 months 95
88, 98
1 dose ≤7 months, 1 dose 8-11 months, 1 dose months
100
88, 100
2 doses ≤7 months, 1 dose months 98
75, 100
3 doses ≤7 months, 1 dose months
94, 100
1 dose 7-11 months, 2 doses months
83, 100
Whitney et al., Lancet 2006;368:

34. Absolute changes in rates of invasive pneumococcal disease among children aged <5 years, by state, 2005 vs
Moore, IDSA 2006

35. Trends in clinical syndromes among children <5 years, 1998-2005
CDC, Unpublished, 2006

36. Trends in clinical syndromes among adults aged >65 years, 1998-2005
CDC, Unpublished, 2006