Pneumococcal polysaccharide vaccination for adults: New perspectives for Europe

Abstract

Vaccination is the only public-health measure likely to reduce the burden of pneumococcal diseases. In 2010, a group of European experts reviewed evidence on the burden of pneumococcal disease and the immunogenicity, clinical effectiveness and cost-effectiveness of vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23). They also considered issues affecting the future use of PPV23 and pneumococcal conjugate vaccines in the elderly and adults at high risk of pneumococcal disease. PPV23 covers 80-90% of the serotypes responsible for invasive pneumococcal disease in Europe. Primary vaccination and revaccination with PPV23 are well tolerated, induce robust, long-lasting immune responses in elderly adults and are cost effective. Ensuring protection against pneumococcal disease requires monitoring of the changing epidemiology of pneumococcal serotypes causing invasive pneumococcal disease and improving vaccine coverage. In the future, it will be critically important for pneumococcal vaccination recommendations for elderly adults to be based on comparative evaluations of PPV23 and newer pneumococcal conjugate vaccines with regard to their long-term immunogenicity, clinical effectiveness and cost-effectiveness.

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10.1586/ERV.11.99
Pneumococcal diseases continue to be an impor-
tant public health problem throughout the world
[1–4]. Although >90 different capsular polysaccha-
ride serotypes of Streptococcus pneumoniae have
been identified, approximately 20 are responsible
for >70% of cases of invasive pneumococcal disease
(IPD) occurring in all age groups. Vaccination is
the only public health measure likely to reduce the
burden of pneumococcal diseases [4].
Two types of pneumococcal vaccine are availa-
ble. The 23-valent pneumococcal polysaccharide
vaccine (PPV23) is used in adults and children
>2 years of age. By contrast, pneumococcal con-
jugate vaccines (PCVs) are currently used only
in children <5 years of age. Indications for using
PCV in adults are under review by regulatory
and public health officials.
The introduction of 7-valent PCV (PCV-7)
vaccination programs for children has dramati-
cally reduced the incidence of pneumococcal
diseases in children, and the highest disease bur-
den is now seen in elderly adults [5,201]. Although
policies for PPV23 vaccination of elderly and
‘at-risk’ adults have been introduced in almost all
European countries, coverage rates among target
populations remain low [6]. Consequently, the mor-
bidity and mortality associated with pneumococcal
diseases in these groups remain high.
In November 2010, a group of experts met to
examine the current status of pneumococcal vac-
cination of elderly and at-risk adults in Europe.
The group reviewed recent evidence on the bur-
den of pneumococcal disease, the immunogenic-
ity, clinical effectiveness and cost–effectiveness
of PPV23 vaccination and issues related to the
future use of PPV23 and PCVs in these groups.
Burden of pneumococcal diseases
S. pneumoniae causes a broad range of diseases:
severe and life-threatening IPD (bacteremia,
meningitis and bacteremic pneumonia), non-
invasive pneumonia, as well as otitis media
and other infections of the upper respiratory
tract [2, 3,7] . Each year, approximately 1.6 mil-
lion people throughout the world die from
pneumo coccal diseases, up to 1 million of them
David S Fedson†1,
Laurence Nicolas-
Spony2, Peter Klemets3,
Mark van der Linden4,
Agostinho Marques5,
Luis Salleras6 and
Sandrine I Samson2
157 Chemin du Lavoir, 01630 Sergy
Haut, France
2Sanofi Paste ur MSD, Lyon, France
3Hospital District of Helsinki and
Uusimaa, Por voo Hospital, Department
of Internal Medicine, Por voo, Finland
4Department of Medical Microbiology,
National Reference Centre for
Streptococci, Universit y Hospital RWTH
Aachen, Germany
5Faculty of Medicine, Porto University,
Porto, Portugal
6Department of Public Health, School
of Medicine, Universit y of Barcelona,
Spain
†Author for correspondence:
Tel.: +33 450 991 306
dfedson @wanadoo.fr
Vaccination is the only public-health measure likely to reduce the burden of pneumococcal
diseases. In 2010, a group of European experts reviewed evidence on the burden of pneumococcal
disease and the immunogenicity, clinical effectiveness and cost–effectiveness of vaccination
with 23-valent pneumococcal polysaccharide vaccine (PPV23). They also considered issues
affecting the future use of PPV23 and pneumococcal conjugate vaccines in the elderly and
adults at high risk of pneumococcal disease. PPV23 covers 80–90% of the serotypes responsible
for invasive pneumococcal disease in Europe. Primary vaccination and revaccination with PPV23
are well tolerated, induce robust, long-lasting immune responses in elderly adults and are cost
effective. Ensuring protection against pneumococcal disease requires monitoring of the changing
epidemiology of pneumococcal serotypes causing invasive pneumococcal disease and improving
vaccine coverage. In the future, it will be critically important for pneumococcal vaccination
recommendations for elderly adults to be based on comparative evaluations of PPV23 and newer
pneumococcal conjugate vaccines with regard to their long-term immunogenicity, clinical
effectiveness and cost–effectiveness.
Keywor ds: adults • cost– effec tiveness • effectiveness • elderly • immunogenicity • invasive pneumococcal
diseases • pneumococcal conjugate vaccines • pneumococcal infections • pneumococcal polysaccharide vaccines
• pneumonia • vaccination
Pneumococcal polysaccharide
vaccination for adults: new
perspectives for Europe
Expert Rev. Vaccines 10(8), 1143–1167 (2011)
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Expert Rev. Vaccines 10(8 ), (2011)
children <5 years of age who live in developing countries [1].
In developed countries, the risk of premature death from IPD
is highest in elderly adults [7–9] and in those with underlying
chronic diseases [8 ,10].
Groups at risk of IPD
Several underlying medical conditions and socio-economic factors
increase the risk of IPD. In adults ≥18 years of age, the stron-
gest risk factors are chronic cardiovascular, pulmonary, liver and
kidney diseases, diabetes mellitus, neurological disorders and
defects in immune defenses [7,8,11,12] . Compared with healthy
adults, individuals with chronic heart and lung diseases and dia-
betes mellitus have a three- to six-fold increased risk of IPD, and
those who are severely immunocompromised have a 23–48-fold
increased risk [8]. Adults who have asthma or who smoke tobacco
are also at increased risk for IPD [13,14]. The overall case–fatality
rate reported for pneumococcal bacteremia may reach 15–20%
in young adults, but it increases to 30–40% among elderly adults
despite appropriate antibiotic treatment [1].
In developed countries, the incidence of IPD is bimodal, with a
peak in infants <2 years of age and another peak in elderly adults
(≥65 years of age). In Europe, it is estimated that 50% of the
EU population will be ≥50 years of age by 2050 [15]. Given that
the number of people with chronic conditions will undoubtedly
increase as the population ages, the number of those at risk of
IPD will also increase.
Current incidence of pneumococcal diseases in the USA
& European countries
In the USA in 2009, 9 years after the introduction of PCV-7
vaccination programs for children, the epidemiology of pneumo-
coccal diseases had changed. The annual incidence of IPD had
become higher in adults ≥65 years of age than it was in children
<5 years of age (40/100,000 and 21/100,000, respectively) [202].
In all age groups, the overall incidence of
IPD was 14.3/100,000 population and the
mortality rate was 1.6/100,000 [202].
In European countries, the age distribution
of cases of IPD is similar to that in the USA.
In 2008, the highest notification rates were in
children <5 years of age and in adults ≥65 years
of age (6.96 and 12.10 cases/100,000, respec-
tively) ( Figure 1) . In 2008, however, the over-
all notification rate for IPD in 24 European
countries was 5.2 per 100,000 population:
much lower than that in the USA [201]. The
large variations in reported rates between
European countries were due to differences
in case definitions, reporting methods and
blood-culturing practices, as well as different
national surveillance systems [2,201].
The overall clinical burden of pneumo-
coccal diseases in elderly adults is still dif-
ficult to assess, especially for community-
acquired pneumococcal pneumonia (this
includes both bacteremic and nonbacteremic cases). Nonetheless,
although the burden of IPD alone is under-reported, informa-
tion on its incidence is essential for evaluating the need for
vaccination with PPV23 [2– 4,16].
Pneumococcal serotypes that cause severe disease
Pneumococcal serotypes differ in their potential for colonization,
invasiveness and virulence [17,18]. While the least commonly car-
ried serotypes are the most invasive, the most frequently carried
serotypes are least likely to cause invasive disease [19–21]. Thus,
serotypes with low invasive potential (types 3, 6A, 6B, 8, 19F
and 23F) behave as opportunistic pathogens in at-risk individuals,
whereas serotypes with high invasive potential (types 1, 7F) can act
as primary pathogens in previously healthy individuals [17]. Some
serotypes with low invasive potential can, however, be associated
with high case–fatality rates once they become invasive [22]. For
example, in a large population-based cohort study of patients with
IPD aged ≥5 years of age in Denmark, serotypes 3, 10A, 11A, 15B,
16F, 17F, 19F, 31 and 35F were associated with high mortality [23].
Impact of PCV vaccination on the epidemiology of
pneumococcal diseases
Herd protection, not herd immunity
Since the introduction of PCV-7 vaccination for children in the
USA, Canada and many European and other countries, there have
been dramatic declines in the incidence of IPD caused by PCV-7
serotypes (Ta ble 1) [9,24–27]. This reduction has been observed not
only in vaccinated children but also among unvaccinated children
and adults, including the elderly. This indirect effect of PCV-7
vaccination reflects what should be called ‘herd protection’, not
‘herd immunity’. A well known example of herd immunity is the
protection associated with oral polio vaccination; vaccine virus
shed by vaccine recipients infects non vaccinated contacts who
then develop active immunity of their own. This does not occur
0
3
6
9
12
15
5–140–4 15–24 25–44 45–64 >65
Age group (years)
Cases/100,000 population
Men
Women
Figure 1. Notification rates for invasive pneumococcal disease by age and sex in
17 European countries in 2008 (n = 12,427).
Reproduced with permission from [201]. © European Centre for Disease Prevention
and Control.
Fedson, Nicolas-Spony, Klemets et al.

www.expert-reviews.com 1145
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Table 1. Impact of 7-valent pneumococcal conjugate vaccine on the incidence of invasive
pneumococcal disease.
Study
(year)
Country, year of PC V-7
introduction, dose schedule
Pre-PCV-7 rate of
IPD/100,000 population
Post-PC V-7 rate of
IPD/100,000 population
Change (%) Ref.
Pilishvili et al.
(2010)
USA
(eight sites: California, Georgia,
Maryland, Minnesota, New
York, Oregon, Tennessee,
Connecticut)
Late 2000
3+1 dose schedule
1998–1999 (n = 4048)
All ages
All types: 24.4
VT: 15.5
Non-VT: 6.1
Age: <5 years
All types: 98.7
VT: 81.9
Non-VT: 6.8
Age: ≥65 years
All types: 60.1
VT: 33.7
Non VT: 18.3
2007 (n = 2576)
All ages
13.5
1
7.9
Age: <5 years
23.6
0.4
10.3
Age: ≥65 years
37.9
2.7
22.5
All ages
-45
-94
+29
Age: <5 years
-76
-100
+51
Age: ≥65 years
-37
-92
+23
(19A: +144)
[25]
Kellner et al.
(2009)
Canada
(Calgary)
End of 2002
3+1 dose schedule
1998–2001 (n = 419)
Age: 6–23 months
(n = 55)
All types: 77.7
VT: 66.4
Non-VT: 11.3
Age: 65– 84 years
(n = 108)
All types: 36.2
VT: 22.1
Non-VT: 14.1
2003–2007 (n = 660 )
Age: 6–23 months
(n = 18)
18
9
8
Age: 65– 84 years
(n = 104)
23.9
4.8
18.8
Age: 6–23 months
-77 (p < 0.001)
-86 (p < 0.001)
-29 (p = 0.61)
Age: 65– 84 years
-34 (p = 0.003)
-78 (p < 0.001)
+34 (p = 0.14)
[9]
Vestrheim
et al.
(2010)
Norway
July 2006
2+1 dose schedule
2004 –2005 (n = 92†)
Age: <5 years
All types: 35.9
VT: 26.9
Age: ≥65 years
VT: 42.4
Non-VT: 33.3
2008 (n = 29†)
Age: <5 years
9.9
1.4
Age: ≥65 years
24
40.6
Age: <5 years
-72.4†
-95†
(non-VT: stable)
Age: ≥65 years
-43.3†
+22†
[26]
Rodenburg
et al. (2010)
The Netherlands
June 2006
3+1 dose schedule
06/2004– 06/2006
(n = 1225)
All ages
All types: 15
VT: 7
Non-VT: 8
Age: <2 years
All types: 34.5
VT: 24.3
Non-VT: 10.1
Age: ≥65 years
All types: 58.8
VT: 28.2
Non-VT: 30.6
06/2006– 06/2008
(n = 1304)
All ages
15.9
6.9
9.1
Age: <2 years
22.5
8
14.5
Age: ≥65 years
60.2
27.9
32.4
All ages
Stable: no significant
change
+13.7 (p = 0.02)
Age: <2 years
-35 (p = 0.006)
-67 (p < 0.0001)
+43.5
Age: ≥65 years
+2†
-1†
+6†
[27]
†% evolution from post-P CV-7 rate of IPD /100,00 0 population compared to pre-PCV-7 rate of IPD /100,000 population.
IPD: Invasive pneumococcal disease; PCV-7: 7-valent pneumococcal conjugate vaccine; V T: Vaccine type.
Pneumococcal polysaccharide vaccination for adults

Expert Rev. Vaccines 10(8 ), (2011)
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with any pneumococcal vaccine. With PCV-7 vaccination, indirect
(herd) protection is the result of reduced nasopharyngeal (NP)
carriage of PCV-7 serotypes in young children and a corresponding
decrease in the transmission of these serotypes to older, unvac-
cinated individuals [9,28–30] . Evidence for this indirect effect is
supported by the reduction in NP carriage of PCV-7 serotypes
observed in unvaccinated Alaskan adults [31]. This reduction has
been accompanied by an increase in the proportion of adults with
non-PCV-7-type carriage. Not surprisingly, the overall rate of NP
colonization by all pneumococcal serotypes has not changed.
Serotype replacement
An increased incidence of IPD caused by non-PCV serotypes
(‘serotype replacement’) has been reported in many settings
[5,2 8] . Reasons for this change include replacement carriage
of previous PCV-7 serotypes with serot ypes unaffected by
vaccine-induced immunity, the unmasking of previous minor-
ity strains (which have a selective advantage after eradica-
tion of PCV-7 serotypes) and serotype (capsular) switching
(which may result in the evasion of host immunity) [32 , 33] .
Some investigators have suggested that other pathogens (e.g.,
Staphylococcus aureus) might expand into the niche formerly
occupied by vaccine serotypes [34] , but this requires further
study. The distribution of disease-causing pneumococcal sero-
types is known to change over time in association with changes
in age, geographical region and the development of antibiotic
resistance [18,32 ,35 –38] . WHO experts, however, have concluded
that PCV-induced serotype replacement explains much of the
recently observed increase in non-PCV serotype disease [5] .
The increase in, and impact of, PCV vaccination on sero-
type replacement differs between countries. In the USA and
several European countries, the most common replacement
90
80
70
60
Serotypes
PCV-7 types
Non-PCV-7 types
19A
50
40
30
20
10
01998 1999
PCV-7 introduced
Children aged <5 years Adults aged >65 years
2000 2001 2002 2003 2004 2005 2006 2007
Cases/100,000 population
Year
40
35
30
Serotypes
PCV-7 types
Non-PCV-7 types
19A
25
20
15
10
5
01998 1999
PCV-7 introduced
2000 2001 2002 2003 2004 2005 2006 2007
Cases/100,000 population
Year
Figure 2. Evolution of invasive pneumococcal disease incidence by serotypes among children aged <5 years and adults
aged ≥65 years in the USA, 1998–2007. PCV-7: 7-valent pneumococcal conjugate vaccine.
Reproduced with permission from [25]. © Pilishvili T, Lexau C, Farley MM, Hadler J, Harrison LH, Bennett NM, Reingold A, Thomas A,
Schaffner W, Craig AS, Smith PJ, Beall BW, Whitney CG, Moore MR; Active Bacterial Core Surveillance/ Emerging Infections Program
Network.
Table 1. Impact of 7-valent pneumococcal conjugate vaccine on the incidence of invasive
pneumococcal disease (cont).
Study
(year)
Country, year of PC V-7
introduction, dose schedule
Pre-PCV-7 rate of
IPD/100,000 population
Post-PC V-7 rate of
IPD/100,000 population
Change (%) Ref.
Ardanuy
et al. (2009)
Spain
(Barcelona)
June 2001
3+1 dose schedule
1997–2001 (n = 380)
Age: ≥18 years
All types: 13.9
VT: 5.6
Non-VT: 8.4
Age: ≥65 years
All types: 45.9
VT: 19.6
Non-VT: 26.4
2005 –2007 (n = 366)
Age: ≥18 years
19.5
4.3
15.3
Age: ≥65 years
56.2
12.3
43.9
Age: ≥18 years
+40 (p < 0.001)
-23 (p = 0.056)
+81 (p < 0.001)
Age: ≥65 years
+23 (p = 0.053)
-37 (p = 0.020)
+67 (p < 0.001)
[24]
†% evolution from post-P CV-7 rate of IPD /100,00 0 population compared to pre-PCV-7 rate of IPD /100,000 population.
IPD: Invasive pneumococcal disease; PCV-7: 7-valent pneumococcal conjugate vaccine; V T: Vaccine type.
Fedson, Nicolas-Spony, Klemets et al.

www.expert-reviews.com 1147
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serotype is 19A (Figu re 2) . This serotype has emerged as an impor-
tant cause of IPD, and isolates are often resistant to multiple anti-
biotics [25,32, 38–4 0]. Other emerging non-PCV-7 serotypes include
types 1, 3, 5 and 7F [9,24, 27].
The extent to which NP colonization with nonvaccine serotypes
accounts for an increasing proportion of pneumococcal disease is
uncertain, but it will undoubtedly be an important consideration for
the future use of pneumococcal vaccines in elderly and at-risk adults
[41]. Understanding the trends in serotype distribution will ensure
that pneumococcal vaccines for elderly adults include newly emer-
gent serotypes responsible for most cases of severe pneumococcal
disease [4,42].
Antibiotic resistance of pneumococcal serotypes
Over the past 30 years, antimicrobial resistance among S. pneu-
moniae has escalated dramatically, and 15–30% of isolates now
exhibit multidrug resistance to ≥three classes of antibiotics [43].
Worldwide, six serotypes (types 6A, 6B, 9V, 14, 19F and 23F)
account for >80% of penicillin- or macrolide-resistant S. pneu-
moniae invasive isolates [43]. In Europe, high rates of penicillin-resis-
tant pneumococci have been recorded in France and Spain, whereas
Germany, Switzerland and the UK have been less affected [203]. The
reasons for these differences are not well understood. Antibiotic
resistance has complicated empiric treatment for suspected pneumo-
coccal infections, resulting in an increase in treatment failures and
medical costs [33,44] and providing another reason for using PPV23.
Pneumococcal vaccination of adults
PPV23 coverage of circulating serotypes
The 23-valent pneumococcal polysaccharide vaccine contains
25 µg of each of the 23 pneumococcal capsular polysaccharide
antigens (types 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14,
15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F) [13]. In the USA,
PPV23 now includes only 65% of serotypes that cause IPD [25],
whereas in Canada, PPV23 covers 84% of invasive serotypes
[9]. In Europe, PPV23 includes 81–91% of the serotypes that
cause IPD [45–47,203] . By comparison, in Europe, 13-valent PCV
(PCV-13) includes 65–77% of the serotypes responsible for IPD
(mean difference, 15%; Table 2) [45–47,203]. Furthermore, PPV23
includes several S. pneumoniae serotypes associated with high IPD
case–fatality rates [23].
Efficacy & effectiveness of PPV23 vaccination in
preventing IPD & pneumonia
Physicians and health officials often turn to meta-analyses to pro-
vide them with a single source of authoritative information on the
efficacy and effectiveness of PPV23. One of the most recent is a
systematic review conducted by the Cochrane Collaboration [48].
This study determined that PPV23 vaccination was significantly
effective in preventing IPD in adults. In ten prospective clinical
trials that included 35,483 patients, the pooled estimate of vaccine
efficacy was 74% (odds ratio [OR]: 0.26; 95% CI: 0.15–0.46).
In five observational studies involving 59,748 older adults, the
pooled estimate of vaccination effectiveness in preventing IPD
was 68% (OR: 0.32; 95% CI: 0.22–0.47).
Despite many clinical trials of PPV23 conducted over the past
decades, its efficacy is still controversial. Most of the uncertainty
has focused on the prevention of pneumococcal pneumonia
(nonbacteremic and bacteremic cases combined) [1]. Conflicting
data from individual prospective efficacy trials reflect several
methodological problems [2 ,3, 16]. For example, sample sizes in
some trials were too small to demonstrate statistically signifi-
cant differences in outcomes [16]. Selection of suitable end points
also presented problems: the diagnosis of IPD is highly spe-
cific, but the incidence of the disease is low, whereas all-cause
community-acquired pneumonia (CAP) is frequent, but the
Table 2. Coverage of invasive pneumococcal disease serotypes by 23-valent pneumococcal polysaccharide
vaccine versus 13-valent pneumococcal conjugate vaccine.
Study (year) Country and year
of PCV-7
introduction
Time
period
Age
(years)
Isolates
(n)
Serotype coverage Ref.
PPV23
(%)
PCV-13
(%)
Difference
PPV23−PCV-13 (%)
Pilishvili et al.
(2010)
USA
Late 2000
2006–2007 ≥65 1432 64.7 49.9 14.8†[25]
Kellner et al.
(2009)
Canada
End of 2002
2007 ≥16 175 83.4†66.7†17.4†[9]
Varon et al.
(2009)
France
2003
2008 ≥16 786 80.8 65.4 15.4†[203]
Imöhl et al.
(2009)
Germany
2002
2003–2006 ≥16 519 91.1 76.7 14.4†[45]
Imöhl et al.
(2010)
Germany
2002
2002–2006 ≥16 1659 88.7 76.3 12.4†[46]
Trotter et al.
(2010)
UK
2003
1996–2006 All ages 52,579 91.6 NA NA [47]
†% difference between PPV23 serotypes coverage and P CV-13 serotypes coverage.
NA: Not applicable; PCV-7: 7-valent pneumococcal conjugate vaccine; PCV-13: 13-valent pneumococcal conjugate vaccine; PPV23: 23-valent pneumococcal
polysaccharide vaccine.
Pneumococcal polysaccharide vaccination for adults

Expert Rev. Vaccines 10(8 ), (2011)
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Table 3. Observational studies of 23-valent pneumococcal polysaccharide vaccination in preventing invasive pneumococcal disease in
elderly adults.
Study (year) Location Design Study population Subgroups VE (%) [95% CI] Ref.
Forrester et al.
(1987)
USA (Denver) Indirect cohort study
26 vaccinated/
63 unvaccinated
Men hospitalized with IPD (mean age: 63.7 years) All -21 [-221–55] [51]
Sims et al.
(1988)
USA (Pennsylvania) Case–control
(n = 122:244)
Immunocompetent persons aged ≥55 years admitted to
hospital with pneumococcal bacteremia, meningitis or
bacteriologically confirmed pneumococcal infection
Mean age: 69.5 years
All All types: 70 [37–86] [52]
Shapiro et al.
(1991)
USA (Connecticut) Case–control
(n = 1054:1054)
All patients admitted to hospital (n = 2108)
Mean age: 67.6 years
All
Immunocompetent
persons (n = 808)
VT: 56 [42–67]
VT: 61 [47–72]
[53]
Butler et al.
(1993)
USA (CDC) National surveillance
study
Indirect cohort
Patients with IPD aged ≥2 years (n = 2837)
Median age: 57 years (vaccinated patients)
All
Immunocompetent
persons aged
≥65 years (n = 443)
VT (PPV23): 60 [30 –77]
VT (PPV23 + PPV14):
75 [57–85]
[54]
Farr et al.
(1995)
USA
(Charlottesville)
Case–control
(n = 85:152)
Individuals aged ≥2 years (at-risk group)
Mean age: 58.2:57.7 years
All All types: 81 [34–94] [55]
Benin et al.
(2003)
USA Case–control
(n = 108:330)
Indirect cohort
(n = 278)
Navajo adults aged ≥18 years
Median age: 58.6:58.8 years
PPV23 vaccination in 62% of cases and 64% of controls
All
All
26 [-29–58]
35 [-33–69]
[56]
Jackson et al.
(2003)†
USA (Washington) Cohort Community-dwelling members of a state health plan aged
≥65 years (n = 47,365)
All
IPD cases (n = 61)
Immunocompetent
persons (n = 38,207)
IPD cases (n = 39)
All types: 44 [7–67]
All types: 54 [13–76]†
[57]
Hedlund et al.
(2003)†
Sweden
(Stockholm
County)
Cohort Residents of Stockholm aged ≥65 years (n = 259,627)
Vaccinated with influenza + pneumococcal vaccines (or
pneumococcal vaccines alone) in 1998 (n = 76,177)
IPD cases (n = 40)
Reduction in hospital
admission for IPD
48 [3–72]†[58]
Andrews
et al. (2004)
Australia (Victoria) Indirect cohort
Screening method
Individuals aged ≥65 years
IPD cases (n = 92) (vaccine related)
PPV23 vaccine coverage rate in ≥65 years: 51% by 2000
All 79 [-14–96]
71 [54–82]
[59]
Dominguez
et al. (2005)
Spain Case–control
(n = 149:447)
Individuals aged ≥65 years
Mean age: 76.7:76.4 years
All
All
Immunocompetent
persons
All types: 70 [48–82]
VT: 72 [50–85]
VT: 78 [50–90]
[60]
†Calculation according to Jack son and Neuzil [3].
C: Central region; IPD: Invasive pneumo coccal disease; NT: Northern territory; PPV14: 14-valent pneumococcal polysaccharide vaccine ; PPV23: 23-valent pneumococcal polysaccharide vaccine; VE: Vaccination
effectiveness; VT: Vaccine -type /vaccine-type related.
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Table 3. Observational studies of 23-valent pneumococcal polysaccharide vaccination in preventing invasive pneumococcal disease in
elderly adults (cont.).
Study (year) Location Design Study population Subgroups VE (%) [95% CI] Ref.
Vila-Corcoles
et al. (2006)†
Spain (Catalonia) Cohort Community-dwelling individuals aged ≥65 years (n = 11,241)
IPD cases (n = 22)
All All types: 40 [-165–78]†[61]
Singleton
et al. (2007)
USA (Alaska) Indirect cohort Alaskan native adults aged ≥20 years
IPD cases (n = 300); PPV23 (n = 97)
Median age: 45 years
All VT: 75 [27–91] [62]
Mooney et al.
(2008)
UK (Scotland) Indirect cohort
Screening method
Vaccination campaign in elderly (aged ≥65 years) in winter
season 2003/2004
IPD cases (n = 170)
All
Adjusted for age/sex
51 [-278–94]
61.7 [45.1–73.2]
[64]
Spindler et al.
(2008)†
Sweden
(Stockholm)
Cohort Residents of Stockholm aged ≥65 years vaccinated over
3-year campaign (n = 101,191)
PPV23 coverage rate: 36% in those aged ≥65 years
IPD cases (n = 566)
All VT: 42.5†[65]
Vila-Corcoles
et al. (2009)
Spain (Tarragona) Population-based
case– control
(n = 304:608)
Individuals aged ≥50 years
Mean age: 73.1:72.7 years
IPD cases (n = 94) Adjusted VE
All types: 66 [34–83]
VT: 76 [34–91]
[66]
Vila-Corcoles
et al. (2010)
Spain (Tarragona) Case–control
(n = 88:176)
Individuals aged ≥60 years
Mean age: 73.2:72.8 years
All IPD (n = 88)
VT IPD (n = 48)
All types: 72 [46–85]
VT IPD: 77 [40 –92]
[67]
Moberley
et al. (2010)
Australia; NT
and C
Screening method
Indirect method
Adults aged 15– 49 years
(87% indigenous) with IPD cases (n = 444)
All NT: 3.4 [-43–35]
C: 67.2 [47–80 ]
NT: 57.3 [15–78]
Unreliable
C: 60 [12–82]
[49]
†Calculation according to Jack son and Neuzil [3].
C: Central region; IPD: Invasive pneumo coccal disease; NT: Northern territory; PPV14: 14-valent pneumococcal polysaccharide vaccine ; PPV23: 23-valent pneumococcal polysaccharide vaccine; VE: Vaccination
effectiveness; VT: Vaccine -type /vaccine-type related.
Pneumococcal polysaccharide vaccination for adults

Expert Rev. Vaccines 10(8 ), (2011)
1150
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sensitivity of a diagnosis for pneumococcal pneumonia is low.
Interpretation of study results has often been confounded by a
failure to understand compound probabilities and the concept of
aggregate effectiveness; PPV23 is actually 23 individual vaccines
[2]. Furthermore, the impact of PPV23 vaccine on IPD in a popu-
lation is highly dependent on vaccine coverage; even when appro-
priate study methods are used, low vaccination effectiveness may
reflect poor vaccine uptake, not poor vaccine performance [49].
Thus, the overall results of individual prospective clinical trials
of PPV23 in elderly adults have not been helpful [16].
Many meta-analyses of these clinical trials have been conducted
to determine whether PPV23 prevents IPD, pneumococcal pneu-
monia, all-cause pneumonia or death [16,48,50]. As with the indi-
vidual clinical trials, the meta-analyses of these trials have also been
problematic [16]. For example, most of them have included studies
of experimental pneumococcal vaccines that were conducted in
the 1940s or trials conducted in younger subjects who are unlike
the elderly adults for whom PPV23 is recommended [16,48,50] . More
importantly, when the numbers of person-years of observation from
each of the individual prospective clinical trials have been aggre-
gated, the total numbers of person-years of observation have still
been insufficient to rule out false negative results [16]. Thus meta-
analyses of prospective clinical trials have not provided [48,50] and
cannot provide [16] reliable evidence for or against the efficacy of
PPV23 in preventing IPD or all-cause pneumonia in elderly adults.
In the absence of clear guidance from prospective clinical
trials and their meta-analyses, observational studies have been
undertaken to determine the effectiveness of PPV23 vaccination
in elderly adults. Almost all of these case–control, retrospective
cohort and indirect cohort studies have shown that PPV23 pro-
vides substantial protection against IPD (Table 3) [49,51–67]. In those
who are immunocompetent, the aggregate effectiveness of vac-
cination (health benefits under the ordinary conditions of clini-
cal practice or public health programs) is between 50 and 80%
[1–3,4 8]. One early case–control study by Forrester et al. failed to
show protection [51]. In this study, the indirect cohort method
used in the ana lysis did not permit consideration of confounding
factors [48], and ascertainment of the vaccination status of cases
and controls was inadequate [68].
Since the late 1990s, four prospective clinical trials have
examined the efficacy of PPV23 (its health benefits demon-
strated under carefully controlled conditions) against pneumo-
coccal pneumonia in adults ( Tabl e 4) . The findings from these
studies have been mixed, with vaccine benefits varying from
none [69–71] to a significant reduction in the risk of pneumonia-
related outcomes [72]. This latter study was conducted in 1006
nursing-home residents considered to be at high-risk for CAP
(mean follow-up, 2.27 person-years). Vaccination with PPV23
reduced pneumococcal pneumonia by 64% and all-cause
pneumonia by 45% [72].
In two observational studies, PPV23 was found to reduce
hospitalizations for all-cause pneumonia by approximately
25% [61,73], and in one study, hospital deaths due to pneu-
monia were reduced by 59% ( Tab le 5) [61]. Another study from
Table 4. Prospective clinical trials of 23-valent pneumococcal polysaccharide vaccine in preventing invasive
pneumococcal disease and community-acquired pneumonia.
Study (year) Location Study population Outcome VE (%) [95% CI] Ref.
Ortqvist et al.
(1998)†
Sweden Immunocompetent persons aged 50 –85 years (n = 691)
Previously discharged following hospitalization for CAP
PPV23 (n = 339)
Placebo (n = 352)
Follow-up not reported
All-cause CAP
Pneumococcal CAP
IPD
-20 [-72–11]†
-28 [-150–34]†
+79 [-77–98]†
[69]
Honkanen
et al. (1999)
Northern
Finland
Individuals aged ≥65 years (n = 26,925)
Individuals who received influenza and pneumococcal
vaccines: 19,549 person-years
Those who received only influenza vaccine:
18,488 person-years
Follow-up: 3.2 years
All pneumonia
Pneumococcal CAP
IPD
-20 [-50–10]
-20 [-90–20]
+60 [-40–90]
[70]
Alfageme
et al. (2006)†
Spain (Seville) Immunocompetent COPD patients aged 61–73 years
Mean age: 65.8 years (vaccine group)
PPV23 (n = 298)
Placebo (n = 298)
Follow-up: 2.7 years
All patients:
all-cause CAP
Age <65 years:
all-cause CAP
Pneumococcal CAP
+24 [-24–54]
+76 [20–93]
+100† (p = 0.061)
[71]
Maruyama
et al. (2010)
Japan Nursing home residents (n = 1006)
Mean age: 84.7 years (vaccine group)
PPV23 (n = 502)
Placebo (n = 504)
Mean follow-up: 2.27 person-years
All-cause CAP
Pneumococcal CAP
+45 [22–61]
+64 [32–81]
[72]
†Calculation according to Jack son and Neuzil [3].
CAP: Communit y-acquired pneumonia; COPD: Chronic obstruc tive pulmonary disease; IPD: Invasive pneumococcal disease; PPV23: 23-valent pneumococcal
polysaccharide vaccine; VE: Vaccine effec tiveness.
Fedson, Nicolas-Spony, Klemets et al.

www.expert-reviews.com 1151
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Australia, however, showed that neither PPV23 nor (surpris-
ingly) influenza vaccination reduced hospitalization for pneu-
monia [74]. In an earlier observational study, PPV23 vaccination
was associated with fewer hospitalizations for pneumonia and
fewer deaths in elderly patients with chronic obstructive pul-
monary disease [75]. Additional benefits of PPV23 vaccination
have been reported in other studies. Among persons hospital-
ized with CAP, previous vaccination with PPV23 was associ-
ated with faster resolution of clinical illness, shorter length
of stay and lower risk of intensive care unit admission and
death [62 ,76] . One recent study reported that hospitalized CAP
patients who had received PPV23 either before hospitalization
or at the time of hospital discharge experienced similar 5-year
outcomes compared with those who had never been vaccinated
[77] . However, this conclusion may not be reliable because
no data were presented on whether previously unvaccinated
CAP patients received PPV23 during the 5-year period fol-
lowing hospital discharge. Finally, unlike the aforementioned
Australian study [74], concomitant use of PPV23 and influenza
vaccines provides elderly adults with added protection against
hospitalization for respiratory, cardiovascular and cerebrovascular
diseases, and death [78, 79] .
The studies showing PPV23 effectiveness in preventing a cer-
tain proportion of cases of CAP are reassuring. Nonetheless, it is
important to understand that preventing IPD alone is a sufficient
reason for vaccinating all elderly adults with PPV23 [2,16, 80].
Table 5. Observational studies of 23-valent pneumococcal polysaccharide vaccination effectiveness against
community-acquired pneumonia in elderly adults.
Study (year) Location Study type Study population Outcome VE (%)
[95% CI]
Ref.
Nichol et al.
(1999)
USA
(Minnesota)
Cohort Members of HMO with chronic
lung diseases (n = 1898)
Aged ≥65 years
Vaccinated with PPV23: 67%
(n = 1280)
All patients:
Hospitalizations for
pneumonia and influenza
Deaths for all causes
43 [16–62]†
(p = 0.005)
29 [9– 44]†
(p = 0.008)
[75]
Fisman et al.
(2006)
USA Cohort Adults aged ≥18 years
hospitalized with CAP
(n = 62,918)
Vaccinated with PPV23: 12%
(n = 7390)
All patients:
Deaths during
hospitalization (adjusted)
50 [41–57]†
[76]
Vila-Corcoles
et al. (2006)
Spain
(Tarragona)
Cohort Community-dwelling individuals
aged ≥65 years (n = 11,241)
Patients with CAP (n = 473):
hospitalized (n = 355; 75%)
outpatients (n = 118; 25%)
All patients:
Overall pneumococcal
pneumonia
Hospitalization for:
All-cause pneumonia
Overall pneumonia
Death due to pneumonia
45 [12–66]
26 [8– 41]
21 [2–34]
59 [28–77]
[61]
Johnstone et al.
(2007)
Canada
(Edmonton,
Alberta)
Cohort Patients aged ≥17 years
hospitalized for CAP (n = 3415)
Patients aged ≥65 years
(n = 2249)
Median age: 75 years
Vaccinated with PPV23: 22%
Aged ≥17 years: death and
ICU admissions
Aged ≥65 years: death and
ICU admissions
39 [8–58]†
(p = 0.02)
37 [3–59]†
(p = 0.04)
[63]
Skull et al.
(2007)
Australia
(Victoria)
Case–cohort
(n = 1952:2927)
Patients aged ≥65 years,
hospitalized for CAP (n = 1952)
54% were vaccinated with PPV23
Hospitalization for all
causes of CAP
0.01 [-16–13]†[74]
Vila-Corcoles
et al. (2009)
Spain
(Tarragona)
Population-
based
case– control
(n = 210:420)
Individuals aged ≥50 years
Mean age: 73.1:72.7 years
Nonbacteremic cases (n = 210)
Nonbacteremic
pneumococcal pneumonia
Adjusted VE (for
age and
alcoholism)
42 [14–61]
[66]
Dominguez
et al. (2010)
Spain
(three
regions)
Case–control
(n = 489:1467)
Individuals aged ≥65 years
admitted to hospital
All patients (including
immunosuppressed):
prevention of
hospitalization for all causes
of pneumonia
23.6 [0.9– 41] [73]
†VE calculations were based on information obtained from each publication.
CAP: Communit y-acquired pneumonia; HMO : Health maintenance organization; ICU: Intensive care unit; PPV23 : 23-valent pneumococcal poly saccharide vaccine;
VE: Vaccination effectiveness.
Pneumococcal polysaccharide vaccination for adults

Expert Rev. Vaccines 10(8 ), (2011)
1152
Review
The immune response to PPV23 in elderly adults & the
question of hyporesponsiveness
Several studies have examined the immunogenicity of primary
vaccination and revaccination with PPV23. Most of them show
that elderly adults mount a statistically significant antibody
response to PPV23. In general, antibody levels decline substan-
tially within 1–2 years of primary vaccination, but they persist
at levels that are, on average, twofold higher than baseline for
5 or more years [81–83] . An early case–control study, however,
found that clinical protection declined for a 5-year period fol-
lowing vaccination [53]. This observation, together with the
decline in antibody levels over time, has led some countries to
recommend a second vaccination for elderly adults and those
at risk.
Table 6. Immunogenicity of a single dose of 23-valent pneumococcal polysaccharide vaccine and
pneumococcal conjugate vaccine in adults.
Study
(year)
Vaccines Population ELISA OPA-OPK Ref.
Short-term Mid-term Short-term Mid-term
Scott et al.
(2007)†
PPV23
PCV-13
Vaccine-naive individuals
aged 18–49 years (n = 30 )
Month 1:
PPV23 < PCV-13
for 3/13 types;
NSA
Month 1:
PPV23 < PCV-13
for 2/13 types;
NSA
[97]
de Roux
et al.
(2008)
PPV23
PCV-7
Patients aged ≥70 years
(n = 219)
Mean age: 75.4 years
Month 1:
PPV23 < PCV-7 for
6/7 types
Month 1:
PPV23 < PCV-7
for 5/7 types
[88]
Musher
et al.
(2008)
PPV23
PCV-7
At-risk patients with a
history of hospitalization
for pneumococcal
pneumonia (n = 81)
Mean age: 63–64 years
Naive to PPV23‡: 24%
4–8 weeks:
PPV23 = PCV-7 for
7/7 types
6 months:
PPV23 < PCV-7 for
3/7 types
4–8 weeks:
PPV23 = PCV-7
for 7/7 types
6 months:
PPV23 < PCV-7
for 3/7 types
[100]
Scott et al.
(2008)†
PPV23
PCV-13
Vaccine-naive individuals
aged 20–50 years (n = 31)
Immunogenicity ana lysis
(n = 29)
Month 1:
PPV23 ≤ PCV-13
for 12/13 types;
NSA
[98]
Dransfield
et al.
(2009)
PPV23
PCV-7‡
Patients with moderate or
severe COPD (n = 120)
Vaccine-naive or no PPV23
within ≥5 years
Patients aged ≥40 years
with moderate or severe
COPD
Month 1:
PPV23 < PCV-7 for
4/7 types
Month 1:
PPV23 < PCV-7
for 4/7 types
[102]
Goldblatt
et al.
(2009)
PPV23
PCV-7
Vaccine-naive or no PPV23
within ≥5 years (n = 599)
Aged 50–80 years
4–6 weeks:
PPV23 > PCV-7 for
1/7 types
PCV-7 > PPV23 for
3/7 types
1 year:
PCV-7 > PPV23 for
1/7 types
[99]
Miernyk
et al.
(2009)
PPV23
PCV-7
Alaskan natives aged
55–70 years (n = 86)
Vaccine-naive
Median age: 57–58 years
Month 2:
PPV23 > PCV-7 for
1/4 types
PPV23 < PCV-7 for
3/4 types
Month 2:
PPV23 = PCV-7
for 4/4 types
[101]
Ridda
et al.
(2009)
PPV23
PCV-7
Frail subjects aged
60–100 years (n = 241)
Mean age: 71–70 years
6 months:
IgG PPV23 = PCV-7
for 4/4 types
Ratio pre/post
PPV23 < PCV-7 for
1/4 types
[103]
†No statis tical ass essment s, presumably because of the small numb er of subjec ts.
‡1-ml dose.
COPD: Chronic obstructive pulmonar y disease; Mid-term: ≥6 months; NSA: No statis tical assessment; OPA: Opsonophagocytic activity; OPK: Opsonophagoc ytic
killing; PCV-13: 13-valent pneumococcal conjugate vaccine; PC V-7: 7-valent pneumococcal conjugate vaccine; PP V23: 23 -valent pneumococcal polysaccharide
vaccine; Short-term: <6 months.
Fedson, Nicolas-Spony, Klemets et al.

www.expert-reviews.com 1153
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Table 7. Immunogenicity of repeated doses of 23-valent pneumococcal polysaccharide vaccine and/or pneumococcal conjugate vaccine
in adults.
Study (year) Study groups Population ELISA OPA-OPK Ref.
Short-term Mid-term Short-term Mid-term
Jackson et al.
(2007)
Comparison with PPV23 in each group
(n = 55, in each group randomized to
four PCV-7:one PPV23)
G1: 0.1 ml PCV-7
G2: 0.5 ml PCV-7 (full dose)
G3: 1 ml PCV-7
G4: 2 ml PCV-7
0.1 ml of PPV23 administered 1 year
after first vaccine
Elderly persons aged
70–79 years
(n = 220)
Mean age: 75 years
Had received PPV23
≥5 years before
enrollment
W 4 after D2:
PPV23 = PCV-7 (0.5 ml)
for 7/7 types
1 year post initial
challenge:
PPV23 = PCV-7
(0.5 ml) for 7/7
types
W 4 post initial
challenge:
PPV23 < PCV-7 (0.5 ml)
for 2/7 types
[104]
de Roux et al.
(2008)
G1: PCV-7/PCV-7 (n = 43)
G2: PCV-7/PPV23 (n = 36 /38 )
G3: PPV23 /PCV-7 (n = 78)
Second vaccine administered 1 year after
first vaccine (n = 159)
Patients aged
≥70 years (n = 219)
Mean age: 75.4 years
M 1 after D2 (at 1 year
of interval):
G1 < initial PCV-7 for
1/7 types
G2 > initial PPV23 for
2/7 types
G3 < initial PCV-7 for
7/7 types
M 1 after D2 (at 1 year
of interval):
G1 > initial PCV-7 for
1/7 types
G2 > initial PPV23 for
6/7 types
G3 < initial PCV-7 for
6/7 types
[88]
Musher et al.
(2008)
G1: PPV23/PCV-7 (n = 44/34)
G2: PCV/ PPV23 (n = 37/32)
Second vaccine administered 6 M after
first vaccine
Patients who survived
pneumococcal
pneumonia (n = 81)
W 4–8 after D2:
G2 > G1 for
3/7 types (p = 0.02)
6 months after D2:
(n = 26)
G1 = G2 for
7/7 types
W 4–8 after D2:
Higher immune response
in G2 but not significant
G1 = G2 for 4/4 types
6 M after
D2:
(n = 25)
G1 = G2
4/4
[100]
Goldblatt et al.
(2009)
G1: PCV-7/PCV-7 (administered 6 M
after first vaccine)
G2: PCV-7/PPV23 (administered 6 M
after first vaccine)
G3: PPV23
G4: PCV-7
Vaccine-naive or no
PPV23 within
>5 years (n = 599)
Aged 50–80 years
4–6 W after D2
(administered 6 months
after D1):
PCV-7/PPV23 >
PCV-7/PCV-7 for
1/7 types
1 year: PCV-7/
PPV23 = PCV-7/
PCV-7 for 7/7 types
[99]
Miernyk et al.
(2009)
G1: PPV23 (n = 28)
G2: PCV-7/PPV23 (administered 2 M
after first vaccine) (n = 29)
G3: PCV-7/PPV23 (administered 6 M
after first vaccine) (n = 29)
Alaskan natives aged
55–70 years (n = 86)
Vaccine-naive
Mean age:
57–58 years
M 2:
PPV23 = PCV-7/PPV23
for 5/5† types
M 6:
PPV23 = PCV-7/PPV23
for 5/5† types
M 2:
PPV23 = PCV-7/PPV23
for 5/5† types
M 6:
PPV23 = PCV-7/PPV23
for 5/5† types
[101]
†Serotype 1 not included in PCV-7.
D: Dose; G: Group ; M: Month; Mid-term: ≥6 months; OPA: Opsonophagocytic activity; OPK: Opsonophagocytic killing; PCV: Pneumococcal conjugate vaccine; PCV-7: 7-valent pneumococcal conjugate vaccine;
PPV23: 23-valent pneumococcal polysaccharide vaccine; Short-term : <6 months; W: Week.
Pneumococcal polysaccharide vaccination for adults

Expert Rev. Vaccines 10(8 ), (2011)
1154
Review
Table 8. Cost–effectiveness studies of 23-valent pneumococcal polysaccharide vaccination.
Study
(year)
Country Design/
perspective
Morbidity/
mortality data
Vaccine
efficacy/
effectiveness
Costs Outcomes Conclusion Comments Ref.
Ament
et al.
(2000)
Five EU
countries:
Belgium,
France,
Scotland,
Spain and
Sweden
Lifetime cohort
model
Healthcare payer
Aged ≥65 years
IPD and PP
IPD: incidence =
29–57/100,000;
mortality = 12–38%
PP: incidence =
451–1167/100,000;
mortality = 9–38%
Identical VE for
IPD and PP =
75% in year 1,
declining to
33% in year 6
(from [53]);
88% serotype
coverage
1995 direct
medical costs of
vaccination +
hospital costs of
disease (excl.
outpatient care)
Base-case: ICER =
€11,000–33,000/QALY
for IPD
Cost saving to €6500/
QALY for PP
SA for IPD with
incidence 50/100,000
and mortality rate 40%:
€3418–5779
Vaccination to
prevent PP and IPD
in elderly highly
cost effective to
cost saving,
encouraging public
health policies for
vaccination of
elderly in Europe
VE against PP
assumed to be
the same as IPD
Concomitant
PPV23
administration
with influenza
vaccine
DR: 3/3%
Grant: Aventis
Pasteur MSD
[108]
Ament
et al.
(2001)
Five EU
countries:
Belgium,
France,
Scotland,
Spain and
Sweden
Extension of [108]
Hypothetical
cohort of 1000
persons aged
≥65 years,
hospitalized with
pneumococcal
infection
Follow-up: 6 years
Same as [108]
Assumption:
incidence of BPP in
15% of patients
VE for IPD =
same as [108]
VE for NBPP =
0–100% (SA)
Same as [108] In each of the five
countries, the CERs
decreased substantially
(by 75%), even when
only a small proportion
(12–15%) of additional
cases of NBPP were
prevented
SA for IPD with
incidence 50/100,000
and mortality rate 20%
CFR even more favorable
Vaccination is
highly cost
effective, even at
very low levels of
clinical
effectiveness
against NBPP
Extension of
Ament ana lysis
done in 2000
[108]
Test uncertainties
around VE
against NBPP (in
addition to VE
BPP)
Grant: Aventis
Pasteur MSD
[115]
Sisk et al.
(2003)
USA Lifetime Markov
model
Societal
Immunocompetent
persons aged
50– 64 years
IPD: average rates of
lab-confirmed cases
from CDC
Incidence: 21–
169/100,000 (from
non-black persons
aged 50–64 years to
black persons aged
≥85 years)
Mortality: 10–21%
(from age 50–64 to
≥85 years)
VE = 93% in
year 1 declining
to 81% in year 6
(from [53])
88.3% serotype
coverage
1995 direct
medical costs of
vaccination +
hospital costs of
disease (excl.
outpatient care)
± long-term
medical costs of
survivors
Base-case when
excluding or including
future medical costs of
survivors, respectively:
• In generally
immunocompetent
persons: $3434–11,416/
QALY (even cost
saving in black
population)
• In high-risk
population: cost
saving to $18,155/
QALY
Extension of
PPV23 vaccination
in 50– 64 years age
group, especially in
black persons, may
be cost effective
Results sensitive to
IPD incidence,
VE and costs
Results confirm the
merit of current
high-risk group
policy and its
effective
implementation
No consideration
of PPV23
revaccination
No consideration
of potential VE
on pneumonia
DR: 3/3%
Grant: CDC
[114]
ABC: Active Bacterial Core; BPP: Bacteremic pneumococc al pneumonia; CER: Cost– effectiveness ratio; CFR: Case –fatalit y rates; DR: Discount rate; Excl.: Excluding ; ICD: International Clas sification of Diseases; ICER:
Incremental cost– effectiveness ratio; Incl.: Including; IPD : Invasive pneumococc al disease; LYG: Life-year gained; MRC: Medical Research Council; NBPP: N onbacteremic pneumococcal pneumonia; NHS: National
Health Ser vice; N IAID: National Institute of Allergy & I nfectious Diseases; PCV-7: 7-valent pneumococcal conjugate vaccine; PP: Pneumococcal pneumonia ; PPV23 : 23-valent pneumococcal polysaccharide vaccine;
QALY: Quality-adjusted life year; SA: Sensitivity analysis; SOP: Standard order program; VE: Vaccination effectiveness.
Fedson, Nicolas-Spony, Klemets et al.

www.expert-reviews.com 1155
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Table 8. Cost–effectiveness studies of 23-valent pneumococcal polysaccharide vaccination (cont).
Study
(year)
Country Design/
perspective
Morbidity/
mortality data
Vaccine
efficacy/
effectiveness
Costs Outcomes Conclusion Comments Ref.
Melegaro
et al.
(2004)
England and
Wales
Lifetime cohort
model
Healthcare
provider (NHS)
Aged ≥65 years
(split into non-high
and high-risk
groups; ~10% of
those aged
≥65 years are high
risk)
IPD: lab-confirmed
disease surveillance
data combined with
hospital database
(incl. meningitis,
septicemia,
pneumonia and
S. pneumoniae as the
cause of the disease,
ICD codes)
Various incidence and
CFR by age, by risk
and by sources of
data
VE in low risk =
65% for
6.5 years
VE in high risk =
20% for 5 years
(from [116])
Various VE and
duration of
protection
tested in SA
2000 medical
costs: primar y
care +
hospitalization +
cost of
vaccination
Base-case high-risk
aged ≥65 years =
£9477/LYG
ICER of all aged
≥65 years = £8504 /LYG
Optimal age seems to
be 70 or 75 years (for
both high- and low-risk
groups)
Routine
vaccination of all
elderly appears to
be more cost
effective than
risk-based strategy
Results depend on
VE, especially in
high-risk group,
IPD
hospitalizations
and CFR
2004: UK
recommendations
were targeted to
high-risk
individuals aged
≥65 years
This ana lysis,
performed by the
Health Protection
Agency, favored
PPV23 use in all
aged ≥65 years
Based on VE
meta-ana lysis
done by same
authors
DR: 3/3%
Grant: MRC and
EU
[116]
Evers et al.
(2007)
Ten EU
countries:
Belgium,
France,
Denmark,
Germany,
Italy, The
Netherlands,
Scotland,
Spain,
Sweden and
England and
Wales
Lifetime cohort
model
Healthcare payer
Aged ≥65 years
IPD: from local studies
(lab-confirmed cases)
and/or reports
Incidence:
29–64/100,000
Mortality: 12–38%
Same as [108]
VE = 75% in
year 1 declining
to 33% in year 6
(from [53])
88% serotype
coverage
1999 direct
medical costs of
vaccination +
hospital costs of
disease (excl.
outpatient care)
Base-case: ICER =
€9239–23,657/QALY
SA with 50/100,000
incidence and 30%
mortality rate =
€3186–11,395
Vaccination to
prevent IPD in
elderly is highly
cost effective,
supportive of a
wider use of the
vaccine in Europe
Update of [108]
Incidence and
mortality in
base-case
under-estimated
Concomitant
PPV23
administration
with influenza
vaccine
DR: 3/3%
Grant: Aventis
Pasteur MSD
[109]
ABC: Active Bacterial Core; BPP: Bacteremic pneumococc al pneumonia; CER: Cost– effectiveness ratio; CFR: Case –fatalit y rates; DR: Discount rate; Excl.: Excluding ; ICD: International Clas sification of Diseases; ICER:
Incremental cost– effectiveness ratio; Incl.: Including; IPD : Invasive pneumococc al disease; LYG: Life-year gained; MRC: Medical Research Council; NBPP: N onbacteremic pneumococcal pneumonia; NHS: National
Health Ser vice; N IAID: National Institute of Allergy & I nfectious Diseases; PCV-7: 7-valent pneumococcal conjugate vaccine; PP: Pneumococcal pneumonia ; PPV23 : 23-valent pneumococcal polysaccharide vaccine;
QALY: Quality-adjusted life year; SA: Sensitivity analysis; SOP: Standard order program; VE: Vaccination effectiveness.
Pneumococcal polysaccharide vaccination for adults

Expert Rev. Vaccines 10(8 ), (2011)
1156
Review
Table 8. Cost–effectiveness studies of 23-valent pneumococcal polysaccharide vaccination (cont).
Study
(year)
Country Design/
perspective
Morbidity/
mortality data
Vaccine
efficacy/
effectiveness
Costs Outcomes Conclusion Comments Ref.
Merito
et al.
(2007)
Italy
(Lazio
region)
5-year cohort
model
Healthcare payer
Aged >64 years
IPD (bacteremic
pneumococcal
pneumonia and
meningitis): from
hospital database
and surveillance local
data
Incidence (corrected):
1–52/100,000 (from
age 65–74 years
[meningitis] to
≥85 years
[pneumonia] )
Case–fatality rate:
9–40% (from age
65–74 years
[pneumonia] to
≥85 years
[meningitis])
VE = 80, 67 and
46% in the first
3 years (in
65–74-, 75–84-
and ≥85-year-old
age groups,
respectively)
declining to 71,
53 and 22%,
respectively, in
years 4 and 5
(from [53])
96% serotype
coverage
2001
healthcare
costs (incl.
vaccination
costs):
outpatient +
inpatient
Base-case with vaccine
coverage from 65% in
65–74 year olds to 0% in
those aged ≥90 years:
ICER = €34,681/IPD
averted and €23,361/LYG
Ratios sensitive to VE,
IPD incidence and
vaccine coverage
PPV23 vaccination
of those aged
≥65 years likely to
be cost effective;
however, lack of
information on VE
and incidence of
VE led to great
variability in ICER
Highlights need
for clear case
definition of IPD
Stress VE in
elderly as major
uncertainty in
countries with
low incidence of
pneumonia
DR: 0% (health
effects)/3%
(costs)
Grant: none
disclosed
[117]
Middleton
et al.
(2008)
USA
(Pittsburgh)
Lifetime model:
hospital-based
research: increase
of vaccine
coverage rates
Societal
Hospitalized,
aged ≥65 years
IPD: from bacterial
surveillance data
Incidence: 26–
73/100,000 (from
age 65– 69 years to
≥85 years)
Mortality: 14–
31/100,000 (from
age 65– 69 to
≥85 years)
VE = 82% in
year 1 declining
to 15% in year 8
(0 in year 9)
2003 costs of
SOP nurse or
pharmacist-
based + cost of
vaccination,
costs of IPD
hospitalizations
averted
SOP allows increase of
vaccine coverage: +31%
and +15% in the two
hospitals
ICER <$10,000/QALY
PPV23 programs
without physician
order (SOP)
increased coverage
in hospitalized
elderly and are
economically
favorable
compared with
current coverage
Vaccination at
hospitalization
helps to increase
PPV23 coverage
rates in ≥65 years
age group leading
to economically
interesting results
Results may not
be transferable to
other USA
regions,
limitation
attenuated
because both
tertiary care and
community
hospitals
included in the
study
DR: 3/3%
Grant: CDC and
Association for
Prevention,
Teaching &
Research
[133]
ABC: Active Bacterial Core; BPP: Bacteremic pneumococc al pneumonia; CER: Cost– effectiveness ratio; CFR: Case –fatalit y rates; DR: Discount rate; Excl.: Excluding ; ICD: International Clas sification of Diseases; ICER:
Incremental cost– effectiveness ratio; Incl.: Including; IPD : Invasive pneumococc al disease; LYG: Life-year gained; MRC: Medical Research Council; NBPP: N onbacteremic pneumococcal pneumonia; NHS: National
Health Ser vice; N IAID: National Institute of Allergy & I nfectious Diseases; PCV-7: 7-valent pneumococcal conjugate vaccine; PP: Pneumococcal pneumonia ; PPV23 : 23-valent pneumococcal polysaccharide vaccine;
QALY: Quality-adjusted life year; SA: Sensitivity analysis; SOP: Standard order program; VE: Vaccination effe ctiveness.
Fedson, Nicolas-Spony, Klemets et al.

www.expert-reviews.com 1157
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Table 8. Cost–effectiveness studies of 23-valent pneumococcal polysaccharide vaccination.
Study
(year)
Country Design/
perspective
Morbidity/
mortality data
Vaccine
efficacy/
effectiveness
Costs Outcomes Conclusion Comments Ref.
Merito
et al.
(2007)
Italy
(Lazio
region)
5-year cohort
model
Healthcare payer
Aged >64 years
IPD (bacteremic
pneumococcal
pneumonia and
meningitis): from
hospital database
and surveillance local
data
Incidence (corrected):
1–52/100,000 (from
age 65–74 years
[meningitis] to
≥85 years
[pneumonia] )
Case–fatality rate:
9–40% (from age
65–74 years
[pneumonia] to
≥85 years
[meningitis])
VE = 80, 67 and
46% in the first
3 years (in
65–74-, 75–84-
and ≥85-year-old
age groups,
respectively)
declining to 71,
53 and 22%,
respectively, in
years 4 and 5
(from [53])
96% serotype
coverage
2001
healthcare
costs (incl.
vaccination
costs):
outpatient +
inpatient
Base-case with vaccine
coverage from 65% in
65–74 year olds to 0% in
those aged ≥90 years:
ICER = €34,681/IPD
averted and €23,361/LYG
Ratios sensitive to VE,
IPD incidence and
vaccine coverage
PPV23 vaccination
of those aged
≥65 years likely to
be cost effective;
however, lack of
information on VE
and incidence of
VE led to great
variability in ICER
Highlights need
for clear case
definition of IPD
Stress VE in
elderly as major
uncertainty in
countries with
low incidence of
pneumonia
DR: 0% (health
effects)/3%
(costs)
Grant: none
disclosed
[117]
Middleton
et al.
(2008)
USA
(Pittsburgh)
Lifetime model:
hospital-based
research: increase
of vaccine
coverage rates
Societal
Hospitalized,
aged ≥65 years
IPD: from bacterial
surveillance data
Incidence: 26–
73/100,000 (from
age 65– 69 years to
≥85 years)
Mortality: 14–
31/100,000 (from
age 65– 69 to
≥85 years)
VE = 82% in
year 1 declining
to 15% in year 8
(0 in year 9)
2003 costs of
SOP nurse or
pharmacist-
based + cost of
vaccination,
costs of IPD
hospitalizations
averted
SOP allows increase of
vaccine coverage: +31%
and +15% in the two
hospitals
ICER <$10,000/QALY
PPV23 programs
without physician
order (SOP)
increased coverage
in hospitalized
elderly and are
economically
favorable
compared with
current coverage
Vaccination at
hospitalization
helps to increase
PPV23 coverage
rates in ≥65 years
age group leading
to economically
interesting results
Results may not
be transferable to
other USA
regions,
limitation
attenuated
because both
tertiary care and
community
hospitals
included in the
study
DR: 3/3%
Grant: CDC and
Association for
Prevention,
Teaching &
Research
[133]
ABC: Active Bacterial Core; BPP: Bacteremic pneumococc al pneumonia; CER: Cost– effectiveness ratio; CFR: Case –fatalit y rates; DR: Discount rate; Excl.: Excluding ; ICD: International Clas sification of Diseases; ICER:
Incremental cost– effectiveness ratio; Incl.: Including; IPD : Invasive pneumococc al disease; LYG: Life-year gained; MRC: Medical Research Council; NBPP: N onbacteremic pneumococcal pneumonia; NHS: National
Health Ser vice; N IAID: National Institute of Allergy & I nfectious Diseases; PCV-7: 7-valent pneumococcal conjugate vaccine; PP: Pneumococcal pneumonia ; PPV23 : 23-valent pneumococcal polysaccharide vaccine;
QALY: Quality-adjusted life year; SA: Sensitivity analysis; SOP: Standard order program; VE: Vaccination effe ctiveness.
Table 8. Cost–effectiveness studies of 23-valent pneumococcal polysaccharide vaccination (cont).
Study
(year)
Country Design/
perspective
Morbidity/
mortality data
Vaccine
efficacy/
effectiveness
Costs Outcomes Conclusion Comments Ref.
Smith
et al.
(2008)
USA Lifetime Markov
model
Societal
Age 50 or 65 years
for first vaccination
+ revaccinations
10 or 15 years
later (eight PPV23
age-based
strategies)
IPD: from bacterial
surveillance data
Incidence: 16–
73/100,000 (from
age 50–54 to
≥85 years)
Age ≤65 years with
comorbidities:
50–126/100,000
In immuno-
compromised:
83–52/100,000
Mortality:
2–20/100,000 (from
age 50–54 to
≥85 years)
VE in healthy
persons aged 50,
65 or 80 years
was 93, 80 or
67%,
respectively, in
year 1 declining
to 20, 0 or 0%,
in year 10
(base-case, from
expert panel)
VE in immuno-
compromised: 0
in base-case and
25.5% in year 1
declining to 2.5%
in year 10 in high
range (from
expert panel)
2003 direct
medical costs
of vaccination
+ hospital costs
of disease (incl.
deaths) +
disability costs
Base-case with 100%
vaccine uptake:
Vaccination in age group
≤65 years with
comorbidities: US$3341/
QALY
Vaccination in ages 50 to
≥65 years: US$23,120/
QALY
Vaccination at ages 50,
60, 70, 80 years:
US$66,818/ QALY
Actual age- and
risk-based vaccine
uptake: vaccination at 50
and 65 years:
US$17,856/QALY
Present vaccination
(65 years and
younger with
comorbidities) not
favored with
current coverage
rates
Policy vaccination
starting at age 50
with high coverage
rates is clinically
and economically
favored over
current
recommendations
Uncertainties
around PPV23
revaccination
efficacy
First analyses
done in an era of
PCV23 for
routine use in
children
DR: 3/3%
Grant: Margaret’s
Foundation (and
Merck & Co., Inc.)
[110]
Smith
et al.
(2010)
USA 10-year Markov
model (flu vaccine
+ PPV23)
Societal
50-year cohort
(among which
31% are in
high-risk groups
recommended for
vaccination by the
CDC)
Same as [110]
IPD: from bacterial
surveillance data
Incidence: 16–
21/100,000 (from
age 50–54 to
60– 64 years)
≥1 comorbid
condition: 50 –
43/100,000
In immuno-
compromised:
83–53/100,000
Mortality:
2–3/100,000 (from
age 50–54 to
60– 64 years)
Same as [110]
VE in healthy
50-year olds:
93% in year 1
declining to 20%
in year 10
(base-case, from
expert panel)
VE in immuno-
compromised: 0
in base-case and
25.5% at year 1,
declining to 2.5%
in year 10 in high
range (from
expert panel)
2006 direct
medical costs
of vaccination
+ hospital costs
of disease (incl.
deaths) +
disability costs
ICER:
Base-case with 100%
vaccine uptake:
US$37,700/ QALY (flu
vaccine + PPV23) versus
current risk
recommendations
Age- and risk-based
actual vaccine uptake:
US$5312/QALY (flu
vaccine + PPV23) versus
current risk
recommendations
Dual vaccination of
all 50-year olds is
economically
reasonable
Results sensitive to
time horizon
considered
Uncertainties
around PPV23
exact duration of
protection
No dynamic
modeling of
epidemiologic
change due to
PCV-7 use in
children but
PPV23 serotype
coverage from
recent ABC CDC
data
No consideration
of PPV23
revaccination
DR: 3/3%
Grant: NIAID
[111]
ABC: Active Bacterial Core; BPP: Bacteremic pneumococc al pneumonia; CER: Cost– effectiveness ratio; CFR: Case –fatalit y rates; DR: Discount rate; Excl.: Excluding ; ICD: International Clas sification of Diseases; ICER:
Incremental cost– effectiveness ratio; Incl.: Including; IPD : Invasive pneumococc al disease; LYG: Life-year gained; MRC: Medical Research Council; NBPP: N onbacteremic pneumococcal pneumonia; NHS: National
Health Ser vice; N IAID: National Institute of Allergy & I nfectious Diseases; PCV-7: 7-valent pneumococcal conjugate vaccine; PP: Pneumococcal pneumonia ; PPV23 : 23-valent pneumococcal polysaccharide vaccine;
QALY: Quality-adjusted life year; SA: Sensitivity analysis; SOP: Standard order program; VE: Vaccination effe ctiveness.
Pneumococcal polysaccharide vaccination for adults

Expert Rev. Vaccines 10(8 ), (2011)
1158
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All polysaccharide vaccines contain T-cell-
independent antigens, so revaccination with
PPV23 cannot induce an anamnestic booster
response [2,3,84]. Nonetheless, significant antibody
responses to most pneumococcal serotypes have
been observed in elderly persons who have received
a second dose of PPV23 [81–84]. The magnitude of
the antibody responses following revaccination,
however, has sometimes been lower than after
primary vaccination, and this has raised ques-
tions concerning ‘hyporesponsiveness’ [85–88].
For example, 1 year after PPV23 vaccination, a
lower antibody response to PCV-7 was seen in 38
elderly patients (≥70 years of age) in whom anti-
body responses decreased threefold [88]. However,
hyporesponsiveness has also been described after
PCV vaccination in children [89,90]. Furthermore,
NP carriage of a PCV-7 serotype shortly before
or at the time of primary vaccination of children
may also be associated with serotype-specific
hyporesponsiveness to PCV-7 vaccine [90].
The largest studies that have addressed the
question of hyporesponsiveness following revac-
cination with PPV23 were conducted in 1008
adults ≥50 years of age and 120 subjects ≥65 years
of age; no evidence of significant long-term hypo-
responsiveness was found [81,82 ,86 ]. Compared
with baseline, primary vaccination and revacci-
nation of both younger and older subjects resulted
in significant increases in total IgG antibody and
opsonophagocytic activity after 30 and 60 days.
For many serotypes, the level of IgG antibody
were higher after primary vaccination than after
revaccination, results that might be interpreted
as indicating hyporesponsiveness. Nonetheless,
after 1 year, IgG antibody levels in the two groups
had declined to similar levels [81]. After 5 years,
antibody levels in the revaccination group had
returned to baseline levels for this group, but
these levels were similar to those seen 3–5 years
after vaccination in the primary vaccination
group. Moreover, 5 years after revaccination (i.e.,
8–10 years after primary vaccination) antibody
levels were generally twofold higher than those of
vaccine-naive subjects (i.e., baseline levels in the
primary vaccination group) [81]. In another study
of Alaskan adults 55–74 years of age, repeat doses
of PPV23 (up to four doses administered ≥6 years
after the primary dose) were immunogenic and
without evidence of hyporesponsiveness [91].
Revaccination with PPV23 is generally well tol-
erated. Local reactions may be more frequent after
PPV23 revaccination than after primary vaccina-
tion, but they are generally mild, self-limiting and
resolve within 2–3 days [1–3,81,91–93].
Table 8. Cost–effectiveness studies of 23-valent pneumococcal polysaccharide vaccination (cont.).
Study
(year)
Country Design/
perspective
Morbidity/
mortality data
Vaccine
efficacy/
effectiveness
Costs Outcomes Conclusion Comments Ref.
Kawakami
et al.
(2010)
Japan 2-year open-label
randomized clinical
trial (flu vaccine +
PPV23) (n = 391)
versus flu vaccine
only (n = 387)
Aged >65 years
(n = 786)
Primary objectives:
all-cause pneumonia,
hospital admissions
due to all-cause
pneumonia
Secondary objective:
medical costs due to
all-cause pneumonia
Not applicable 2005 and 2006
medical costs
including
vaccination
costs (flu
vaccine +
PPV23) and
pneumonia
care
Significant reduction in
incidence and admissions
of all-cause pneumonia
in >75 age group (but
not in >65 age group) by
36.6 and 41.5%,
respectively, by PPV23
over 2 years
In all subjects,
pneumonia-related costs
were significantly
reduced (by 54%) in
year 1 post PPV23
PPV23 effective in
significantly
reducing
incidence,
hospitalization and
costs of all-cause
pneumonia in >75
age group (over a
2-year period), but
not in those aged
>65 years
Subgroup analyses
show that patients
aged >65 years
with walking
difficulties benefit
the most (versus
cardiac, lung, renal
and chronic
diseases)
Supports
recommendation
of PPV23
combined with
flu vaccine in
those aged
>75 years in
Japan
Higher reduction
in older people
may be partly
explained by
higher incidence
of pneumococcal
pneumonia in
these subjects
Research Grant:
Japanese Ministry
of Health, Labor
& Welfare
[112]
ABC: Active Bacterial Core; BPP: Bacteremic pneumococc al pneumonia; CER: Cost– effectiveness ratio; CFR: Case –fatalit y rates; DR: Discount rate; Excl.: Excluding ; ICD: International Clas sification of Diseases; ICER:
Incremental cost– effectiveness ratio; Incl.: Including; IPD : Invasive pneumococc al disease; LYG: Life-year gained; MRC: Medical Research Council; NBPP: N onbacteremic pneumococcal pneumonia; NHS: National
Health Ser vice; N IAID: National Institute of Allergy & I nfectious Diseases; PCV-7: 7-valent pneumococcal conjugate vaccine; PP: Pneumococcal pneumonia; PPV23 : 23-valent pneumococcal polysaccharide vaccine;
QALY: Quality-adjusted life year; SA: Sensitivity analysis; SOP: Standard order program; VE: Vaccination effe ctiveness.
Fedson, Nicolas-Spony, Klemets et al.

www.expert-reviews.com 1159
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Comparison of PPV23 & PCV
immunogenicity in adults
The immunogenicity of PPV23 and PCV
in adults is affected by variations in sero-
type carriage, pre-existing immunity
and the decrease in immune response
that occurs with advancing age [94] .
Importantly, immune correlates of clinical
protection for both vaccines have not been
defined for adults [1].
The differences in immune responses
of children to PPV23 and PCV are well
known, but comparison of the immuno-
genicity of the two vaccines in adults is
more complicated. No differences in the
kinetics of serum antibodies, circulat-
ing plasma and memory B-cell responses
between PPV23 and PCV-7 have been
found either 28 days or 2 years following
vaccination [95,9 6]. Of ten studies compar-
ing immune responses to a single dose of
PPV23 or PCV (7-valent or 13-valent) in
adults [83, 88,97–103], nine failed to demon-
strate a definite and consistent advantage
of PCV over PPV23, either in antibody
levels or opsonophagocytic activity (Table 6).
Furthermore, immunogenicity studies in
adults given PPV23 or PCV sequentially
(combined schedules included intervals
varying from 4 weeks to 1 year) have failed
to provide convincing evidence that favors one
vaccination schedule or one vaccine over the
other (Table 7) [83,88 ,99–101,104].
Socio-economic studies of PPV
vaccination in adults
Economic burden of pneumococcal
disease in adults
It has been difficult to estimate the economic burden of pneumococ-
cal disease in adults because accurate data on its epidemiology, espe-
cially IPD, and the costs of treatment are not available. For IPD in
adults ≥50 years of age, the direct costs (e.g., those related to drugs,
hospitalization and physician visits) and indirect costs (e.g., the value
of lost work days due to disease-related morbidity) are substantial.
In the USA, the estimated annual direct and indirect costs of IPD
are approximately US$3.7 billion and US$1.8 billion, respectively
[105], and the estimated annual cost of CAP is >US$17 billion [106].
In Europe, the estimated annual costs of pneumo coccal pneumonia
are approximately €10.1 billion, with inpatient care accounting for
€5.7 billion, outpatient care €0.5 billion, drugs €0.2 billion, and
indirect costs (lost work days) €3.6 billion [107].
Cost–effectiveness of PPV23 vaccination
Studies undertaken in the USA and in ten European countries
over the past 10 years have shown that PPV23 vaccination of
elderly adults (≥65 years of age) is cost effective [108–117] . In
European countries, the incremental cost–effectiveness ratios
for preventing IPD alone were calculated to be below well-
accepted thresholds for cost–effectiveness (Ta ble 8 ) . In the USA,
vaccination of those ≥50 years of age may even be cost saving
[114]. Recent observational studies have shown that PPV23 vac-
cination might prevent 20–25% of all cases of CAP in elderly
adults (mentioned previously), and this suggests an even greater
cost–effectiveness for PPV23 vaccination [115]. These cost–effec-
tiveness estimates compare very favorably with the cost–effec-
tiveness of other medical interventions in this age group [2,118] ,
and provide further support for universal PPV23 vaccination
of elderly adults [113].
Uncertainties surrounding estimates of the burden of pneu-
mococcal disease, the clinical effectiveness of PPV23 vaccina-
tion and vaccine coverage undoubtedly affect analyses of its
cost–effectiveness. Nonetheless, these studies provide important
Table 9. European recommendations for 23-valent pneumococcal
polysaccharide vaccination in adults.
Country Age (years) Risk factors
Immunodeficiency†Chronic
illness‡
Institutionalization§
Austria ≥65 Yes Yes NR
Belgium ≥65 Yes (asplenia, HIV ) Yes in ≥50 NR
Denmark NR Yes Yes NR
Finland ≥65 Yes Yes Yes
France NR Yes Yes Yes
Germany ≥60 Yes Yes NR
Greece ≥60 Yes Yes NR
Ireland ≥65 Yes Yes NR
Italy ≥64 (age
groups depend
on regions)
Yes Yes Yes
Luxembourg ≥60 Yes Yes Yes
The
Netherlands
NR Yes Yes NR
Norway ≥65 Yes (asplenia, HIV) Yes NR
Portugal NR NR NR NR
Spain ≥60/65 (age
groups depend
on regions)
Yes Yes Yes
Sweden ≥65 Yes Yes NR
Switzerland ≥65 Yes Yes NR
UK ≥65 Yes Yes NR
Risk group definitions var y between countries.
†Immunodeficiency may include asplenia (func tional or anatomic), decreased splenic func tion (sickle cell
anemia), HIV infec tion, transplants, ly mphoma and so on.
‡Chronic illnesses may include cardiovascular disease, pulmonary disease, diabetes mellitus, renal disease,
liver disease, cerebrospinal fluid leakage, ethylism and so on.
§Institutions refers to nur sing homes, long-term care facilities and so on.
NR: No re commendation.
Pneumococcal polysaccharide vaccination for adults

Expert Rev. Vaccines 10(8 ), (2011)
1160
Review
information to health officials who make vaccination recom-
mendations. When the cost–effectiveness of an existing vac-
cine (e.g., PPV23) is already known, the cost–effectiveness of
a new vaccine (e.g., PCV) must be considered carefully [2,118] .
If a new pneumococcal conjugate vaccine demonstrates a small
incremental increase in clinical effectiveness in elderly adults
but is much more expensive compared with PPV23, increasing
PPV23 coverage in a population might be a more cost-effective
approach for preventing pneumococcal diseases than switching
to PCV.
European recommendations for
PPV23 vaccination
Guidelines for adult vaccination have
been issued by several European scientific
societies. The European Union Geriatric
Medicine Society (EUGMS) and the
International Association of Geriatrics
and Gerontology–European Region
(IAGG–ER) recommend PPV23 vac-
cination for adults ≥60 years of age fol-
lowed by revaccination every 5 years [6,15].
Revaccination is also recommended for
those admitted to nursing homes and for
those who have repeated hospital admis-
sions [6,15]. The European League Against
Rheumatism (EULAR) strongly recom-
mends influenza and PPV23 vaccination
in patients with autoimmune inflam-
matory rheumatic diseases [119]. These
recommendations are similar to those in
the USA, where the Centers for Disease
Control and Prevention (CDC) Advisory
Committee on Immunization Practices
(ACIP) recommends vaccination with
PPV23 for adults aged ≥65 years and for
those in at-risk groups [2,3,13] . In 2010, the
ACIP added a recommendation to vac-
cinate adults with asthma and those who
smoke tobacco [120].
Although recommendations for PPV23
vaccination have been issued in 17 European
countries, the groups regarded as being at
increased risk of invasive disease differ con-
siderably from country to country (Tabl e 9) .
Eight countries recommend routine PPV23
vaccination for all persons ≥65 years of age
and five countries recommend vaccination
starting at a younger age, usually 60 years.
Four countries recommend PPV23 only for
at-risk groups. However, risk-based vaccina-
tion strategies necessitate identifying indi-
viduals with specific diseases, either through
direct contact or computerized registries
[121], and they usually fail to achieve high
coverage levels [122]. In contrast, universal
age-based vaccination strategies are easier to
implement and are more cost effective [116].
They usually achieve higher and broader
levels of vaccine uptake.
Switzerland
Norway
Austria
Italy
Iceland
Sweden
Greece
Belgium
Spain
Ireland
Germany
UK
Finland
France
Portugal
Denmark
The Netherlands
0 500 1000
2123
1607
1488
1280
1220
922
901
721
677
652
587
333
218
583
452
271
49
Cumulative doses distributed per 10,000 persons
1500 2000 2500
Countries
Countries recommending
pneumococcal vaccination
for all elderly people and
those considered ‘at risk’
of pneumococcal infection
Countries recommending
pneumococcal vaccination
only for those considered
‘at risk’ of pneumococcal
infection
Figure 3. Cumulative number of doses of 23-valent pneumococcal polysaccharide
vaccine per 10,000 persons distributed in selected European countries in
2001–2010. The figure shows the cumulative number of doses of pneumococcal vaccine
distributed per 10,000 total population during a 10-year period from 2001 to 2010. For each
European country for each year, the number of doses of PPV23 (regardless of the tradename
Pneumovax® 23 or Pneumo23®) was divided by the total national population for that year,
and the cumulative number of doses obtained by summing these numbers for the 10-year
period. The numbers of doses of PPV23 distributed for each country were extracted from
2001–2010 IMS Health databases and/or internal sales data (Sanofi Pasteur MSD being the
exclusive supplier of both vaccines). Total populations by country were taken from official
national population statistics: Austria: Statistics Austria [207]; Belgium: Statistics Belgium [208];
Denmark: Statistics Denmark [209]; Finland: The Official Statistics of Finland (SVT) [210]; France
INSEE [211]; Germany: Federal Statistical Office (Destatis) [212]; Greece: Hellenic Statistical
Authority (ELSTAT) [213]; Iceland: Statistics Iceland [214]; Ireland: Central Statistics Office
Ireland [215]; Italy: Italian National Institute of Statistics (ISTAT) [216]; The Netherlands:
Statistics Netherlands [217]; Norway: Statistics Norway [218]; Portugal: Eurostat [219]; Spain:
National Statistics Institute (INE) [220]; Sweden: Statistics Sweden [221]; Switzerland: Swiss
Federal Statistical Office [222]; UK: Office for National Statistics [223].
Sources: IMS Health data, Sanofi Pasteur MSD unpublished data, European populations:
national statistics.
Fedson, Nicolas-Spony, Klemets et al.

www.expert-reviews.com 1161
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Table 10. Coverage rates for 23-valent polysaccharide vaccine in selected European countries.
Study (year) Country Population Study design /method Annual VCR
(%)
Cumulative VCR (%)§Ref.
Gavazzi et al.
(2007)
France Aged ≥65 years†Sur vey in geriatric
healthcare facilities
21.9 (up to 2003) [123]
Delelis-Fanien
et al. (2009)
France Aged ≥65 years†2-month survey of GPs 19.6 (up to 2007) [124]
Tiv et al. (2010) France
(two regions)
High-risk adults
aged ≥65 years in
nursing homes
Survey in geriatric nursing
homes
27 (up to 2009) [125]
Spindler et al.
(2008)
Sweden
(Stockholm
County)
Aged ≥65 years National registration
number (active campaign
flu vaccine + PPV23)
36 (end 1998 to end 2001) [65]
Martinelli et al.
(2010)
Italy (Puglia
region)
Aged ≥65 years Data from local health
unit vaccination registers
+ GP validation
≤8 (2005–2007) 26.3 (2000–2004)
31 (2002–2007)
[126]
Zhang et al.
(2007); Begum
et al. (2008)
UK (HPA
surveys
2006/07 and
2007/08)
Aged ≥65 years National survey among
GPs
6.5 (2006/07)
4.6 (2007/08)
66.6 (2003–2007)
69 (2003–2008)
[204, 205]
Bossuyt et al.
(2005)
Belgium Aged ≥60 years‡Data collected via GP
sentinel network
29 (1993–2004) [127]
Tafforeau et al.
(2008)
Belgium High-risk adults
(aged >50 years)‡
and ≥65 years‡
Population-based survey 11 (2003–2008) [206]
Dominguez
et al. (2005)
Spain
(Catalonia)
Hospitalized
patients aged
≥65 years
Case–control
(effectiveness) study
21% in IPD cases
41% in controls
(October 1999 to March 2002)
[60]
Vila-Corcoles
et al. (2006)
Spain
(Tarragona,
Catalonia)
Aged ≥65 years Prospective cohort
(effectiveness) study
44%
(October 1999 to end 2001;
i.e., before start of study)
[61,135]
Mereckiene
et al. (2010)
Ireland High-risk adults
aged ≥65 years
Phone survey among
population
12 (up to 2009/10)
33 (up to 2009/10)
[128]
†National recommendations restrict PPV 23 only for ‘at risk’ groups.
‡PPV23 recommended but not funded.
§Cumulative VCR is calculated as those vaccinated at any time prior to the star t of the observation period plus those in the unvaccinated subpopulation who were
vaccinated within the observation period (sum of the annual VCR over the observation period).
GP: General practitioner; HPA: Health Protection Agency; PPV23: 23-valent p olysaccharide vaccine; VCR: Vaccine coverage rate.
The epidemiology of PPV23 vaccination in Europe
Estimates of PPV23 uptake in Western European countries can
be inferred from the number of vaccine doses distributed in each
country between 2001 and 2010. These estimates highlight great
disparities in PPV23 vaccination (Figur e 3). Higher levels of vaccine
use have been seen in countries with age-based recommendations
and public reimbursement. In some countries with age-based rec-
ommendations, the lack of public reimbursement may explain low
uptake rates (e.g., Austria, Finland, Norway). Countries recom-
mending vaccination only for at-risk individuals are those in which
the use of PPV23 is lowest (The Netherlands, Denmark, Portugal
and France).
In several European countries, survey estimates of PPV23 cover-
age rates in elderly adults (especially in those at risk) vary between
countries, reflecting national recommendations and program
funding (Table 10) [123–128,20 4–206] . In most European countries, cov-
erage rates have been low, ranging between 20 and 30%. The high-
est cumulative coverage rate (over 69%) has been seen in the UK,
where active campaigns to promote PPV23 vaccination for elderly
adults and younger persons at risk were begun in 2003 [204,205].
Strategies for improving PPV23 coverage rates in
elderly adults
Methods to improve PPV23 vaccine coverage require clear vac-
cination program objectives, greater access to and reduced cost of
vaccination, and increased community demand through the use of
reminders, education and public-awareness campaigns. Physician
recommendations are a critical factor in improving PPV23 vac-
cination rates, and incentives for healthcare professionals can also
be important [2,129,130].
Pneumococcal polysaccharide vaccination for adults

Expert Rev. Vaccines 10(8 ), (2011)
1162
Review
Key issues
• Streptococcus pneumoniae causes a broad range of diseases, including serious invasive pneumococcal disease ( IPD).
• Decreasing the burden of IPD in elderly adults should be a priority for European physicians and public health ser vices.
• Vaccination is the only effective measure of preventing pneumococcal disease.
• 23-valent pneumococcal polysaccharide vaccine (PPV23) covers the broadest spectrum of pneumococcal serotypes: 80–90% .
• The aggregate effectiveness of PPV23 in preventing IPD in the elderly is 50–80%.
• PPV23 also reduces the rates of community-acquired pneumonia hospitalization and death in elderly adults.
• Both primary vaccination and revaccination with PPV23 are well tolerated and induce robust and durable immune responses that last
for at least 8–10 years in older adults.
• PPV23 vaccination to prevent IPD in elderly adults is cost effective and may sometimes be cost saving.
• It is important for healthcare providers, public health officials and policymakers to recognize the serious health impact of pneumococcal
disease in older adults, closely monitor the epidemiology of pneumococcal serotypes (especially ‘serotype replacement’) and ensure
increased coverage with PPV23.
One important strategy is to identify missed opportunities
for vaccination. In one study, 92% of unvaccinated patients
who developed IPD had at least one opportunity for vaccina-
tion within the previous 2 years [131]. Vaccination at the time of
hospital discharge could be especially effective. Two-thirds of
patients hospitalized with IPD, pneumococcal pneumonia or
CAP have been discharged from hospital within the previous
5 years, and could be vaccinated at the time of hospital discharge
[2,132]. Standing orders for vaccinating discharged patients can be
especially cost effective [133]. Unfortunately, few of these patients
are ever vaccinated.
Expert commentary
The clinical and economic burden of IPD in elderly adults in
Europe is substantial. Although vaccination is the only effective
way to prevent severe pneumococcal disease, PPV23 coverage
rates among elderly adults in Europe remain low. PPV23 meets
the essential requirements for an adult pneumococcal vaccine. It
provides the broadest spectrum of serotype coverage of any avail-
able pneumococcal vaccine, covering 80–90% of the serotypes
responsible for IPD in Europe. In elderly adults, PPV23 vaccina-
tion prevents 50–80% of cases of IPD requiring hospitalization.
In addition, it prevents approximately 20–25% of cases of CAP in
elderly adults. Both primary vaccination and revaccination with
PPV23 are well-tolerated and induce robust immune responses
in elderly adults that last for at least 8–10 years. Furthermore,
PPV23 vaccination of elderly adults is very cost effective.
Five-year view
Healthcare providers, public health officials and policymakers
need to develop a greater understanding of the serious health
impact of pneumococcal disease in elderly adults. In addition
to increasing vaccine coverage in older adults, they need to
monitor the changing epidemiology of pneumococcal serotypes
causing invasive disease [134]. In the face of these changes, it will
be critically important for health officials to base recommenda-
tions for the use of PPV23 and newer PCVs in elderly adults
on comparative evaluations of their long-term immunogenicity,
clinical effectiveness and cost–effectiveness.
Acknowledgements
The authors thank Sanofi Pasteur MSD, Lyon, France, for supporting the
meeting that led to this report and for providing unpublished data on PPV23
distribution in European countries.
The authors also thank Florence Baron-Papillon (Sanofi Pasteur MSD)
and Suzanne Soum (Sanofi Pasteur MSD) for their assistance in preparing
the manuscript. The authors take sole responsibility for its content.
Financial & competing interests disclosure
All authors attended the expert meeting sponsored by Sanofi Pasteur MSD
November 2010.
David S Fedson received compensation for attending the initial expert
meeting and for writing and reviewing the several drafts of this manuscript.
Within the past year, DSF has lectured on pneumococcal vaccination at
two scientific meetings and received travel compensation and modest hono-
raria. DSF has no other competing interests; he is retired and receives no
salary or consultation fees for his activities. DSF contributed to data col-
lection, ana lysis and interpretation, critical review and final validation of
the manuscript.
Mark van der Linden has received research funding from Wyeth/Pfizer,
GSK, is a member of advisory boards of Wyeth/Pfizer and GSK and is a
consultant for Wyeth/Pfizer, GSK and Sanofi Pasteur MSD. MvL contributed
to data collection, ana lysis and interpretation, critical review and final
validation of the manuscript.
Agostinho Marques and Peter Klemets contributed to the critical review
and final validation of the manuscript.
Luis Salleras has received travel expenses and honoraria for lectures and round-
tables from Sanofi Pasteur, GSK, Pfizer, Novartis and Crucell. LS contributed
to data ana lysis and critical review and final validation of the manuscript.
Laurence Nicolas-Spony and Sandrine I Samson are employed by Sanofi
Pasteur MSD. LNS and SIS contributed to data collection and critical
review of the manuscript.
The authors have no other relevant af filiations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
Funded writing assistance was utilized in the production of this manu-
script from Communigen Ltd (Oxford, UK). No other writing assistance
was utilized in the production of this manuscript.
Fedson, Nicolas-Spony, Klemets et al.

www.expert-reviews.com 1163
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