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Vaccine 27 (2009) 3285–3290
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/vaccine
Immunization with the 7-valent conjugate pneumococcal vaccine: Impact
evaluation, continuing surveillance and future perspectives
Angela Bechini, Sara Boccalini, Paolo Bonanni∗
Department of Public Health – University of Florence, Florence, Italy
a r t i c l e i n f o
Available online 5 February 2009
Pneumococcal conjugate vaccine
Direct and indirect protection
Correlates of protection
a b s t r a c t
diseases caused by vaccine serotypes in children less than 2 years-old. Its effectiveness was confirmed
under routine use in the US, Canada and several European countries.
Disease surveillance and several studies showed that population indirect protection outweighs direct
protection of immunized subjects. A substantial impact was also confirmed on pneumonia and acute
A limited increase in IPD caused by non-vaccine serotypes was registered to date, but far below the
magnitude of the beneficial reduction in IPD due to vaccine serotypes. This fact underpins the need for
ongoing improved surveillance. New tests based on PCR for the identification and typing of pneumococci
represent a very interesting alternative to traditional cultural tests that should be evaluated in the near
The World Health Organization has recognized the priority to introduce PCV into the routine infant
immunization schedule in all countries, due to the extremely high yearly mortality toll for pneumococcal
diseases in the world (1.6 million deaths estimated).
These new products need to be compared with the existing vaccine, following WHO recommendations
regarding correlates of protection, in order to show their possibility to substitute the current vaccine
obtaining the same impressive level of efficacy and effectiveness.
© 2009 Elsevier Ltd. All rights reserved.
Streptococcus pneumoniae (pneumococcus) is the causative
agent of a constellation of diseases, among which otitis media,
pneumonia, sinusitis, sepsis and meningitis are the most impor-
tant in terms of frequency and/or severity. On the other hand,
carriage of S. pneumoniae is extremely frequent, since 20–60% of
healthy children and 5–10% of healthy adults carry the germ in
their nasopharynx . Pneumococcal diseases show maximum
incidence at extreme ages of life, being particularly frequent and
dangerous in infants and young children (up to the age of 5 years)
and in the elderly.
More precisely, infants and young children are most susceptible
to pneumococcal disease between 3 and 24 months of age, i.e. after
maternal antibodies wane and before they can develop a protective
∗Corresponding author at: Department of Public Health – University of Florence
– Viale G.B. Morgagni, 48 – 50134 Florence, Italy. Tel.: +39 055 4598511;
fax: +39 055 4598935.
E-mail address: firstname.lastname@example.org (P. Bonanni).
At least 90 different pneumococcal serotypes exist based on
the composition of the capsular polysaccharides. However, most
of pediatric invasive diseases are caused by a limited number
of serotypes. In the United States, studies performed in the pre-
vaccine era showed that serotypes 4, 6B, 9V, 14, 18C, 19F and 23F
were responsible of about 80% cases of invasive diseases, thus
prompting the development of a 7-valent Pneumococccal Conju-
gate Vaccine (PCV-7) containing such serotypes . Furthermore,
it was also evident that antibiotic resistance, an emerging prob-
lem in all countries, was linked primarily with 5 pneumococcal
serogroups, namely 6, 9, 14, 19 and 23, i.e. a subset of the same
types included in the 7-valent vaccine [3–5].
The present review aims at revising the results obtained to date
in countries that implemented routine infant immunization with
in terms of evaluation of new vaccines with increased number of
serotypes that are about to be introduced in the coming years.
2. Impact of PCV-7 on invasive pneumococcal diseases
The first phase 3 clinical trial of the conjugate pneumococ-
cal vaccine performed on about 38,000 subjects at the Northern
0264-410X/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.
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A. Bechini et al. / Vaccine 27 (2009) 3285–3290
California Kaiser Permanente health maintenance organization
(randomized to receive either vaccine or placebo in a 1:1 propor-
tion) showed the excellent performance of this vaccine. As a matter
of fact, the first evaluation gave 100% efficacy in both the per pro-
tocol population (0 versus 17 invasive disease cases in vaccinees
and control group, respectively), and in the intention-to-treat pop-
ulation (0 versus 22 cases in the two populations, respectively)
A follow-up of the same study performed about 1 and a half
year later confirmed an excellent efficacy, since the per protocol
population efficacy was 97.7% (95% c.i.: 86.7–98.9%), while it was
94.5% in the intention-to-treat population (95% c.i.: 83.2–98.9%).
Routine vaccination of all children under 2 years of age was
recommended in USA in 2000, followed by a rapid increase of
immunization coverage. The first evaluation of impact in the field
based on the US sentinel surveillance system called Active Bacte-
rial Core (ABCs) showed that 2 years after the recommendation for
routine childhood immunization had been issued, the incidence of
invasive diseases had decreased from 188/100,000 to 59/100,000
in vaccinated children, a statistically highly significant difference.
However, in addition to this expected result, the incidence of
invasive pneumococcal diseases (IPD) significantly decreased also
in other age groups, with statistically significant differences in the
age groups 20–39 and 40–64 years, but particularly in the elderly
(65+years), where the incidence turned from 60.1/100,000 in 1996
to 49.5/100,000 in 2001 .
Following this first study, an impressive number of papers were
published with accumulating evidence that the PCV-7 vaccine had
impacted not only on IPD, but also on the relative hospitalisa-
tion rates in both vaccinees and other unvaccinated age groups
A recent evaluation by the US Centers for Disease Control (CDC)
covering the period 1998–2005 showed that the overall decrease
of incidence of IPD due to vaccine types in subjects aged <5 years
was −80.2/100,000 (a 98% change), with a concomitant increase of
non-vaccine types IPD of 4.9/100,000 (+29%), thus resulting in a net
overall decline of incidence of −75.5/100,000 (a 77% decrease). For
cases (14,200 PCV-7-type cases prevented minus 1200 additional
non-PCV7-type cases) were prevented in 2005 among US children
aged <5 years. During 2001–2005, an estimated 62,000 cases of IPD
were prevented among children aged <5 years .
An important issue regards the impact of vaccination on the
nasopharyngeal carriage of other non-vaccine pneumococcal types
and its link with the so-called ‘replacement disease’ (i.e. the possi-
bility that the ecologic niche left free by vaccine-type pneumococci
immunization with PCV-7 was no or little change in the over-
all colonisation because non-vaccine types replaced vaccine types
in the nasopharynx . However, surveillance data of the ABCs
network in children aged <2 years in the period 1998/1999–2005
showed that the baseline incidence of 160/100,000 vaccine-type
related IPDs decreased to 2/100,000 at the end of the follow-up,
meaning a decline of −158/100,000 (98%), with a further added
impact on vaccine-related serotypes (−12/100,000). This positive
impact was only partially shaded by an increase of non-vaccine
type pneumococci, among which the surge of IPD due to serotype
19A was of particular importance (+10/100,000), while other non-
vaccine types increased of 8 cases/100,000. The overall net decline
of pneumococcal IPD cases was −152/100,000.
Similar results, but with more evident replacement disease,
were recently reported in France, where the most recent evalua-
tion (2007) of coverage in 6–12 year-old infants was 56% , but
only about 44% the year before (2006). From 2001/2002 to 2006,
cases per 100,000, and the incidence of pneumococcal bacteraemia
decreased from 21.8 to 17.5 cases per 100,000 in children under the
age of 2 years.
Regarding vaccine strains, the incidence of pneumococcal
meningitis and bacteraemia decreased from 20.4 to 6.0 cases per
100,000, while the incidence of pneumococcal meningitis and bac-
teraemia due to non-vaccine strains increased from 9.4 to 17.5
cases per 100,000 in this time period. The 19A strain was partic-
ularly important among those increasing after PCV-7 introduction,
(p=0.03) and from 11% to 27% in bacteraemia cases (p<0.001).
The incidence in older children and adults did not decrease .
An added value of PCV-7 is the impact on pneumococcal antibi-
otic resistance. A study on the annual incidence of IPD caused
by penicillin-non-susceptible pneumococci in children aged ≤2
years between 1996 and 2004 in USA showed a decline from
50–60/100,000 in the pre-vaccine era to 5–10/100,000 after the
introduction of routine immunization .
of studies, including those on the annual incidence of invasive dis-
50 and 64 years, 29% in the age range 65–74 years, 35% between 75
and 84 years, and 28% in subjects ≥85 years .
The relevance of community protection afforded by PCV-7 was
recognized in 2005 by the Centers for Disease Control (CDC), who
highlighted that in 2003, in the USA, 20,459 estimated cases of IPD
had been prevented through an indirect effect versus 9140 cases
directy avoided in vaccinees .
Also the cost-effectiveness profile of PCV-7 was deeply changed
by the evidence of its indirect effects. An economic model devel-
oped before herd effects were detected had provided a cost of
$112,000 per life-year saved in the US context. After incorporating
the reductions in IPD for non-vaccinated individuals, the vaccine
averted 109,000 cases of IPD at a cost of $7500 per life-year saved.
The Authors concluded that PCV-7 might even be cost-saving if
the indirect effect were extended to reducing pneumonia in the
non-vaccinated population .
3. Impact of PCV-7 on pneumonia and otitis media
Pneumonia represents one of the most dreadful diseases in the
world, and is responsible of about 20% of all deaths in children <5
years. As a matter of fact, pneumonia kills more children than any
than 2 million children under 5 years of age die from pneumo-
nia each year, yet few headlines report the effect of such disease
on children’s lives . However, pneumonia is caused by differ-
ent aetiological agents, and assessing the proportional role of S.
monia is often treated with antibiotics before hospital admission,
thus making the isolation and typing of the responsible agent very
difficult or impossible.
A first evaluation of the impact of PCV-7 on pneumonia was
performed during the already cited Northern California Kaiser Per-
manente Efficacy trial, where different pneumonia outcomes were
evaluated: all clinical cases of pneumonia regardless of any radio-
logical findings, and clinical pneumonia with infiltrates outside the
criteria, efficacy was only 4.9%, but taking into account the Chest
X-Ray (CXR) evidence, efficacy increased to 20.5%.
nia and positive CXR according to WHO reading criteria, efficacy
further raised to 30.3% .
Also a Cochrane revision of different studies on efficacy of PCV-
7 against pneumonia confirmed an average 22% efficacy (95% c.i.
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A. Bechini et al. / Vaccine 27 (2009) 3285–3290
With regard to otitis media, initial studies gave controversial
quent disease, but also to the possibility that replacement disease
occurs more frequently for this outcome .
A systematic review conducted in 2004 showed that aggregated
results of four studies yielded a 9% reduction of children with acute
study showed a substantial reduction of otitis media in vaccinated
children living in Tennessee and New York after at least 3 doses of
PCV-7 (23%) .
The impact of immunization on visit rates due to otitis media
was also evaluated in USA. Such rate declined by 20% in children
aged <2 years comparing the period before and after the imple-
mentation of universal immunization with PCV-7 . For these
reasons, in the summary of product characteristics approved by
the European Agency of Medicines (EMEA) for PCV-7, pneumonia
and otitis media were added as pneumococcal diseases for which
vaccination is indicated .
4. The World Health Organization (WHO) position paper on
pneumococcal coniugate vaccine for childhood
In March 2007, WHO issued an important position paper to
jugate vaccination in all countries of the world. As a matter of fact,
WHO recognizes that diseases caused by S. pneumoniae are a major
million people die of pneumococcal disease every year; this esti-
mate includes the deaths of 0.7–1 million children aged <5 years,
most of whom live in developing countries.
Serotypes included in PCV-7 cover 65–80% of serotypes associ-
ated with invasive pneumococcal disease among young children in
western industrialized countries. However, this coverage varies in
different populations, and may be lower in many developing coun-
tries. Other pneumococcal conjugate vaccines with wider serotype
coverage, including a 10-valent vaccine and a 13-valent vaccine, are
in the late stages of development.
Recognizing the heavy burden of pneumococcal disease occur-
ring in young children and the safety and efficacy of PCV-7 in this
age group, WHO considers that it should be a priority to include
this vaccine in national immunization programmes, particularly
in countries where mortality among children aged <5 years is
>50/1000 live births or where >50,000 children die annually.
When the vaccine is first introduced into routine childhood
immunization programmes, a single catch-up dose of PCV-7 may
be given to previously unvaccinated children aged 12–24 months
and to children aged 2–5 years who are at high risk.
Countries are encouraged to conduct appropriate surveillance
for pneumococcal disease in order to establish a baseline measure-
ment of disease and to monitor the impact of vaccination. This is
particularly important in those developing countries that will be
prevalence of HIV infection or other conditions known to increase
the risk of pneumococcal disease.
Careful observation is necessary owing to the possibility that
conjugate vaccines could result in a significant shift in prevail-
ing pneumococcal serotypes that cause serious disease. To date,
however, vaccine-induced replacement of prevailing pneumococ-
cal serotypes has not been found to be a significant problem with
respect to invasive disease. Once pneumococcal vaccines offering
broader serotype coverage become available, countries using PCV-
7 should assess whether it would be helpful to switch to these
vaccines. This assessment should be based on the distribution of
serotypes causing invasive pneumococcal disease in the affected
population and the likely additional benefit to be gained from
Fig. 1. Incidence of IPD in children living in the province of Florence, Italy, between
broadening the spectrum of vaccine serotypes. The introduction
of pneumococcal conjugate vaccines with broader coverage will be
facilitated if PCV-7 is already in use .
5. Continuing surveillance
The evidence for substitution by non-vaccine pnemococcal
strains in the nasopharynx, and the partial occurrence of replace-
ment disease after implementation of universal immunization
programmes with PCV-7, underline the importance of continuing
and further implementing the surveillance of diseases caused by S.
In order to detect all cases of IPD irrespective of already started
antibiotic therapies at the time of sample collection, a new PCR
method (Real Time or RT-PCR) was recently described by Azzari et
PCR-based assays for direct detection of pneumococci from
clinical samples do not require viable bacteria and reach a very
high sensitivity, representing an important tool in the diagnosis of
invasive pneumococcal infections . However, up to now, PCR-
based methods on clinical samples have been used to discriminate
between pneumococci and other pathogens  but not for pneu-
mococcal serotyping. S. pneumoniae serotyping was performed on
RT-PCR positive samples through a sequential multiplex PCR on
DNA extracted from biological samples as for RT-PCR. Among 92
children (80 with pneumonia, 8 with meningitis/sepsis, 4 with
arthritis), 4 cases of IPD were diagnosed both by culture and real-
time PCR and 18 cases exclusively by molecular methods.
The sensitivity of molecular methods was significantly higher
than that of cultural methods. The incidence of IPD in children
below 2 years of age was 11.5/100,000 and 51.8/100,000 by cul-
tural and molecular methods, respectively (Fig. 1). Pneumococcal
serotyping by multiplex sequential PCR was obtained in 19/22
samples. The much higher yield of molecular methods compared
with classical cultural methods, together with the possibility to use
whole heparinated blood for DNA testing make this new method
an extremely interesting alternative for the monitoring of invasive
diseases due to S. pneumoniae as well as for other bacterial agents.
6. Criteria for the evaluation of new vaccines under
Vaccines with an increased number of serotypes are presently
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A. Bechini et al. / Vaccine 27 (2009) 3285–3290
pneumococcal conjugate vaccine efficacy studies and the pooled studies weighted for number of study subjects (NCKP: Northern California Kaiser Permanente). Source: .
valent and a 13-valent conjugate pneumococcal vaccines should be
available on the market within the next couple of years. The former
contains the 7 types included in PCV-7, plus 1, 5 and 7F, while the
latter, in addition to types included in the 10-valent vaccine, also
are in early stages of development. Approaches based on pneu-
mococcal proteins like pneumolysin, PspA, PspC, Lyt A are other
possibility in need of further studies.
In this paragraph we will concentrate on the vaccines expected
to be available in the near future, and on the criteria needed for
As a matter of fact, efficacy trials of the new vaccines are uneth-
ical when an effective vaccine (PCV-7) is available. Therefore, we
need to find a suitable correlate of protection in order to infer the
efficacy of the new vaccines by measuring the level of such corre-
A correlate of protection is defined as ‘...a specific immune
response to a vaccine that is closely related to protection against infec-
tion, disease or other defined end point’ .
Protection against S. pneumoniae is provided by opsono-
phagocytic activity mediated by protective antibodies measurable
by ELISA tests. The potential issue related to the use of these
tests is the reported modest relationship between the ELISA IgG
concentrations and opsono-phagocytic titres . However, IgG
antibody concentrations [C] as measured by ELISA appears to be
the best parameter to use as the primary criteria for licensure of
new vaccine formulations for the following reasons: (1) IgG is the
desired immune response; (2) the methodology for measuring it is
validated in infants; (3) a bridge to efficacy data has been estab-
lished; and (4) a cross-laboratory standardization process has been
completed. The functional opsono-phagocytic assays will provide
critical supplementary data for the serotypes included in PCV-7
and primary data on additional serotypes in new vaccines. Other
serologic tests can provide additional descriptive data, but have
not yet been standardized and have not proven to be predictive
of protective efficacy .
that the formula used for the evaluation of vaccine efficacy
(V.E.) (V.E.=1−probability of the disease in the vaccinated
group/probability of disease in the control group) can be trans-
formed into the following formula for pneumococcal vaccines:
V.E.=1−% of vaccinated subjects with antibody concentration
<protective level/% of control subjects with antibody concentration
In other words, the relative risk of IPD is the same as the rel-
ative risk of having antibody concentration less than the minimal
This is possible when 3 assumptions are made:
(a) antibody concentration [C] after the primary series of three
doses of vaccine predicts protection (post-dose three assess-
the antibody concentrations and functional activity are lower
than after the fourth dose, and the highest age-specific disease
risk is between the third and fourth doses);
(b) the relationship between risk of disease and antibody concen-
tration is expressed in a step-wise rather than in a continuous
function, whereas in reality the relationship is continuous;
(c) the protective antibody concentrations are assumed to be sim-
ilar for all pneumococcal serotypes and therefore a single
estimate is used for all types (since IPD are rather rare events,
the confidence intervals around the point estimates of efficacy
remain too wide to be useful in estimating protective concen-
trations for each serotype) [32–33].
When V.E. is known, protective [C] may be determined directly
from the Reverse Cumulative Distribution Curves (RCDC) of the
antibody concentrations of the vaccinated group and the control
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A. Bechini et al. / Vaccine 27 (2009) 3285–3290
Estimated protective antibody concentration ([C]prot) to 7 vaccine type pneumococcal capsular polysaccharides (source: ).
StudyVE observed (%)Estimated [C]prot(mg/ml, 95% CI)
0.20 (0.03, 0.67)
0.68 (0.03, 6.00)
0.35 (0.09, 0.89)
0.35 (0.11, 0.85)
The bold numbers are Geometric Mean followed by 95% CI (GM, 95% CI).
of the variability of the vaccine efficacy estimate and the serology
data (Table 1).
Therefore, a WHO committee elected to accept a single protec-
tive concentration applicable to all seven serotypes in the PCV-7
vaccine using pooled efficacy and pooled serology results from the
three main controlled studies (see Fig. 2). A WHO technical report
and control of new pneumococcal conjugate vaccines.
The World Health Organization established that data from three
double blind controlled trials in Northern Californian, American
to derive a protective concentration of 0.35?g/ml for anticapsular
antibodies to the 7 serotypes in the current conjugate vaccine.
Opsonophagocytic antibody titres were available from two of
the three studies, and analysis of the data showed that antibody
best with protective efficacy.
Direct clinical comparison of the registered (established) vac-
cine with the new one is the preferred method for evaluating new
The percentageof responders
immunization antibody concentration is above the threshold)
should be used as the criterion to determine non-inferiority.
For the serotypes present in a registered vaccine, the percentage
of responders to each serotype in the new formulation or combina-
tion should be compared with the percentage of responders to the
same serotype in the registered vaccine in the same population.
Registration of products in which one or more serotypes do not
meet non-inferiority criteria should be decided on an individual
basis . These criteria should not be used to evaluate vaccines
against other clinical end-points, e.g. pneumonia and otitis media.
As a matter of fact, the protective level for nasopharyngeal car-
riage and acute otitis media depends from antibody concentration
with non-linear relationship. The protective cut-off level is specific
for each serotype and varies considerably among them. However,
the antibody levels required for protection against acute otitis
media and carriage are certainly higher than dose needed for IPD
coccal diseases caused by vaccine serotypes in children less than 2
years-old. Its effectiveness was confirmed under routine use in the
US, Canada and several European countries.
indirect protection outweighs direct protection of immunized sub-
jects. A substantial impact was also confirmed on pneumonia and
acute otitis media.
A limited increase in IPD caused by non-vaccine serotypes was
registered to date, but far below the magnitude of the beneficial
reduction in IPD due to vaccine serotypes. This fact underpins the
need for ongoing improved surveillance. New tests based on PCR
for the identification and typing of pneumococci represent a very
interesting alternative to traditional cultural tests that should be
evaluated in the near future.
The World Health Organization has recognized the priority to
introduce PCV into the routine infant immunization schedule in
all countries, due to the extremely high yearly mortality toll for
pneumococcal diseases in the world (1.6 million deaths estimated).
Conjugate vaccines with additional serotypes are in advanced
stage of development or under evaluation.
These new products need to be compared with the existing
vaccine, following WHO recommendations regarding correlates
of protection, in order to show their possibility to substitute the
current vaccine obtaining the same impressive level of efficacy and
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