Abstract
Streptococcus pneumoniae causes different types of acute, invasive and non-invasive clinical infections, being the most frequently detected pathogen responsible for community-acquired pneumonia. Pneumococcal pneumonia is accompanied by bacteraemia in 10-30% of cases. Streptococcus pneumoniae is gaining resistance to the in vitro activity of several antimicrobial agents and, even if questions remain regarding the clinical impact of this phenomenon, more and more reports indicate that antibiotic resistance can lead to more treatment failures if not higher mortality. Use of the 23-valent anti-pneumococcal vaccine appears to offer subpotimal protection against pneumococcal disease, particularly among high-risk adult populations. Vaccination against S. pneumoniae with new conjugate vaccines seems to be the most promising field for real improvement in the management of pneumococcal infections in adults.
Keywords
Introduction
Streptococcus pneumoniae is one of the most important causes of morbidity and mortality worldwide, being the first aetiological pathogen of pneumonia [
1
, 2
]. Streptococcus pneumoniae is part of the commensal flora of the upper respiratory tract and colonizes the nasopharyngeal niche. Colonization seems to be an important feature because pneumococcal disease will not occur without the preceding nasopharyngeal colonization [3
]. The clinical spectrum of pneumococcal infection ranges from acute otitis media and sinusitis to pneumonia. When the organism invades normally sterile sites such as the bloodstream and meninges, the resulting forms of pneumococcal disease are classified as invasive.In nature, S. pneumoniae is present in at least 92 different serotypes. The serotypes differ greatly in nasopharyngeal carriage prevalence, invasiveness and disease incidence. The vast majority of the burden of pneumococcal disease is associated with a rather restricted number of serotypes. The most commonly encountered are serotypes 3 (16.9%), 19 (10.7%) and 14 (7.5%). Serotypes have different pathogenicities. Serotype 2 frequently causes invasive disease, Serotypes 3, 4, 6A, 6B, 7, 9N, 9V, 11, 12, 14, 15A, 15F, 16, 18C, 22, 23A, 23B, 31, 33 and 35 are associated with mortality [
4
, 5
].Epidemiology and clinical burden
Most of the burden of pneumococcal infections in adults is in fact related to pneumonia. Community-acquired pneumonia (CAP) is a major respiratory health disease with high prevalence in the general population, clinical heterogeneity and variable severity. Both in the USA and in Europe, CAP is the most frequent cause of death from infection and has implications for healthcare systems worldwide [
6
, 7
, 8
]. The reported incidence of CAP varies considerably from country to country and study to study, but reports are consistent in identifying a progression in rate with increasing patient age [9
]. Given that in Europe the population mean age is sharply increasing, it is to be expected that over the next decades an important increase of pneumonia hospital admissions and
costs will take place [10
]. Altered immune competence is an additional risk factor for pneumonia, with evidence of human immunodeficiency virus (HIV)-infected subjects presenting a 25-fold increase in bacterial pneumonia compared with the general population [11
].Infection with influenza virus increases the risk of developing S. pneumoniae pneumonia and pneumococcal invasive disease [
12
, 13
]. It has been estimated that secondary pneumococcal infections may have caused as much as 20% mortality during the 1918-19 influenza pandemic, as demonstrated in a review of autopsy series, which found that 27% of blood cultures were positive for S. pneumoniae [14
]. A study conducted during the 2009 H1N1 pandemic found a significant increase in pneumococcal hospitalizations at the time of highest pandemic influenza activity [15
]. Individuals aged 5-19 years, who have low baseline levels of pneumococcal disease, experienced the largest relative increase in pneumococcal hospitalizations (ratio 1.6; 95% CI 1.4-1.7), whereas the largest absolute increase was observed among individuals aged 40-64 years. In contrast, there was no excess disease in the elderly.A recent review tried to define the burden of CAP among adults in Europe [
16
]. Forty-six primary articles were analysed and S. pneumoniae was reported as the most frequently isolated pathogen, being isolated in 38% of outpatient cases, 27% of inpatient cases, and 28% of intensive-care pneumonia cases. Among the different European countries, pneumococcal identification rates were lowest in Italy (11.9%), and highest in Finland (68.3%) [16
]. Worldwide pneumococcal pneumonia morbidity and mortality rates are still remarkable. The mortality rate ranges from 6.4% to >40% in the different setting of outpatients, inpatients and intensive-care patients [17
]. Increasing age is also a risk factor for pneumonia mortality.Pneumococcal pneumonia is accompanied by bacteraemia in 10-30% of cases and it is then classified as invasive. The incidence of invasive pneumococcal disease is affected by a number of factors, including, smoking status, immune status, age and geographical location. Reported incidence rates of invasive pneumococcal disease (IPD) in European and US studies indicate an overall incidence between 11 and 23.2 per 100 000 population, which rises to 16.2-59.7/100 000 population in adults aged over 65 years [
18
, 19
, 20
, 21
]. These studies were conducted between 1995 and 2003, before widespread use of pneumococcal conjugate vaccine in children, which has been associated with a ‘herd immunity’ effect causing decreased IPD incidence in unvaccinated adults (see later) [22
, 23
]. In subjects with chronic medical conditions IPD incidence rises further to 176-483/100 000 [20
], and reaches 342-2031/100 000 population among immunosuppressed patients [20
, 24
]. Even when appropriate antibiotic treatment is instituted, IPD mortality remains high, involving 10-25% of patients [25
].Economic impact of pneumococcal disease
The White Book edited by the European Respiratory Society estimated that the annual financial burden of pneumonia in the 51 countries of the WHO Europe region is higher than z.euro;10 billion, with inpatient care accounting for around z.euro;6 billion annually. Pneumonia accounts for >30% of hospital days in respiratory units and loss of work days generate indirect costs of more than z.euro;3.5 billion [
26
]. The median direct costs of treating patients hospitalized with CAP in Germany were $1333 per case [8
]. Major contributors to the total direct costs were expenses for staff and bed occupancy. In an Italian investigation on the costs of respiratory diseases, the average cost/year for treating a single CAP patient was estimated to be z.euro;1586.04 [27
]. A study conducted in Spain calculated the mean direct costs for CAP management as z.euro;196 for outpatients and z.euro;1553 for inpatients [28
]. In many of these economic-based studies microbiological work up was not rigorously standardized and cost associations for specific pathogens are therefore difficult. Nonetheless, considering that S. pneumoniae is thought to cause 30-50% of CAP cases, it may be assumed that a sizable portion of these costs may be attributable to pneumococcal disease.One recent study specifically investigated the economic burden of pneumococcal disease [
29
]. This was a cost analysis performed in the USA using a model combining age-specific and risk-group-specific data on rates and costs of disease. The authors found that the annual clinical and economic burden of pneumococcal disease among US adults aged over 50 years was about $3.7 billion in total direct costs, and $1.8 billion in total indirect costs.Antibiotic resistance
The existence of antibiotic-resistant S. pneumoniae strains is a well-known phenomenon across most countries worldwide. Despite escalation in antimicrobial resistance rates worldwide over the past decades [
30
], mortality rates for IPD (including pneumonia and bacteraemias) have not increased [31
]. Treatment failures because of drug-resistant strains have been reported but a causative role has not been convincingly established. Drug resistance is a microbiological laboratory finding and the exact impact of this 'in vitro' phenomenon on treatment outcomes in clinical practice is still debatable.Two different systematic reviews and meta-analyses of the available data on the implications of S. pneumoniae penicillin resistance on outcome reach different conclusions. Metlay [
4
] evaluated 15 studies involving over 7500 patients with pneumococcal pneumonia. Twelve of the fifteen studies analysed by the authors failed to demonstrate any relationship between antibiotic resistance and mortality. Conversely, Tleyjeh et al. [32
] systematically reviewed ten prospective cohort studies involving >3400 patients, and observed a 19.4% mortality rate among penicillin-non-susceptible S. pneumoniae infections as opposed to 15.7% among penicillin-susceptible pneumococcal infections. In this review, the combined adjusted relative risk of short-term mortality for penicillin-non-susceptible vs. susceptible pneumococcus was 1.29 (95% CI 1.04-1.59).In interpreting these studies it must be kept in mind that mortality associated with pneumococcal infection is influenced by a number of clinical factors independent of antimicrobial susceptibility, such as host factors (e.g. age, immunosuppression, comorbidities), and virulence factors (e.g. capsular subtype). These issues are not easily accounted for in clinical studies, and may bias attempts to correlate decreased antibiotic susceptibility with outcome parameters. In addition, systematic reviews and meta-analyses are most informative when based on randomized controlled clinical trials. However, in this setting, because of logistical and ethical considerations, all the analysed studies are observational, albeit prospective in design, introducing concerns regarding quality assessment.
Macrolide resistance in S. pneumoniae may have greater clinical importance than penicillin resistance. Epidemiological data show a striking increase in pneumococcal resistance rates to macrolides worldwide. Reports from Germany, USA and other European and Asian countries showed a resistance rate that varies from 18% to 75% [
33
, 34
, 35
]. Most of the published studies did not show any increase of mortality related to macrolide non-susceptibility, but several studies showed an increased rate of failures and possible breakthrough bacteraemia during macrolide treatment of macrolide-resistant pneumococcal pneumonia [36
, 37
, 38
, 39
].Failure of first-line empirical therapy leads to an increase of costs related to longer hospital stay and the use of second-line antibiotics [
33
]. In fact, a study conducted in the Veneto Region in Italy showed that the cost of second-line antibiotics after initial failure accounted for z.euro;1342 per patient [40
].To contain the emergence and spread of drug-resistant pneumococcal strains, judicious use of antimicrobials has been suggested to avoid a selective advantage for these antimicrobial-resistant organisms. Given that six serotypes (i.e. 6A, 6B, 9V, 14, 19F, 23F) account for >80% of penicillin-resistant or macrolide-resistant S. pneumoniae strains worldwide [
41
], use of vaccines providing activity towards the above strains may also prove a valuable tool in curbing further increases in resistance rates.Clinical impact of vaccines on pneumococcal infections
Development of an effective anti-pneumococcal vaccine has been a slow process, mainly because of the poor immunogenicity of bacterial surface polysaccharides, which are the primary target of opsonizing antibodies. In the early 1980s, a vaccine containing purified capsular polysaccharides from 23 of the known pneumococcal serotypes (PPV23) (see Table 1) was marketed in the USA, and later in Europe. The serotypes involved are responsible for 85-90% of IPD cases among adults [
42
]. Polysaccharides are T-cell-independent antigens that generally stimulate short-lived B-cell responses by driving the differentiation of B cells to plasma cells to produce antibodies [43
]. New memory B cells are not produced in response to most polysaccharide vaccines. Following a single dose of PPV23, serotype-specific IgG, IgA and IgM are produced, with the IgG2 subclass dominating the IgG response. Responses are age-dependent and serotype-dependent. Antibody responses to vaccination are generally lower in elderly persons than in younger adults. As a result of the T-cell-independent immunological response, there is no anamnestic or booster response on revaccination [43
].TABLE 1Serotypes covered by main polysaccharide and conjugate pneumococcal vaccines
| Vaccine | Included serotypes |
|---|---|
| PPV23 | 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F |
| PCV7 | 4, 6B, 9V, 14, 18C, 19F, 23F |
| PCV10 | 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 23F |
| PCV13 | 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F |
Given the considerable burden of morbidity and mortality associated with pneumococcal disease, several observational studies and randomized controlled trials (RCTs) have been conducted to evaluate polysaccharide vaccine efficacy as a preventing agent. The fact that the impressive number of 17 meta-analyses, the last of which was published in 2009 [
44
], have reviewed these trials between 1994 and 2009 testifies that there are many areas of uncertainty regarding true vaccine efficacy. The most commonly evaluated and clinically relevant outcome measures include IPD, all-cause pneumonia, pneumococcal pneumonia and mortality (all-cause or pneumonia-related). All-cause pneumonia rates are often used as a surrogate marker for pneumococcal pneumonia given the low yield of diagnostic tests for definitive identification of S. pneumoniae as the aetiological agent.All told, there seems to be little doubt regarding the protective action of the polysaccharide vaccine against IPD in healthy adults and, to a lesser extent, among elderly individuals. For example, the 2008 Cochrane review [
45
] analysed 15 RCTs (involving >48 000 participants) and included seven observational studies (involving >62 000 subjects) that provided adjustment for important confounding factors. Meta-analysis of the RCTs found that the polysaccharide vaccine reduced the risk of IPD with an OR of 0.26 (95% CI 0.15-0.46). This correlated with a protective vaccine efficacy of 74% (95% CI 56-85%). The protective effect does not seem to apply to patient subgroups because it was absent in adults with chronic illness, a vulnerable population for pneumococcal disease. Meta-analysis of the seven non-RCTs showed vaccine protective efficacy towards IPD of 52% (95% CI 37-61%), which was maintained in the subgroup of elderly immunocompetent patients.Polysaccharide vaccine efficacy against other outcomes such as pneumonia or mortality is less clear. In the Cochrane 2008 meta-analysis [
45
], efficacy against all-cause pneumonia among RCTs gave an OR of 0.71 (95% CI 0.52-0.97), which was judged as inconclusive because of substantial heterogeneity among the included studies. Likewise, the study failed to demonstrate evidence for polysaccharide vaccination effectiveness against all-cause mortality. The most recently published meta-analysis in the field is noteworthy in that data were analysed according to the methodological quality of the trials [44
]. Once again, the authors found no apparent efficacy of polysaccharide vaccines for presumptive pneumococcal pneumonia, all-cause pneumonia or mortality. One observational study that reported some benefit in preventing pneumococcal pneumonia found that best efficacy was registered in healthy adults, but PPV23 failed to protect the elderly and populations at risk such as patients with chronic illness and immune suppression [46
]. The latest RCT using PPV23 was conducted among 1006 elderly nursing home residents (mean age 85 years) in Japan [47
]. The authors found a protective vaccine efficacy of 44.85% (95% CI 22.4-60.8, p <0.0006) against all-cause pneumonia and a vaccine efficacy of 63.8% (95% CI 32.1-80.7, p <0.0015) against pneumococcal pneumonia. The study has been criticized for methodological reasons [48
]. In the study, significantly more participants with pneumococcal pneumonia died in the placebo group than in the vaccine group: 35.1% (13/37) vs. 0% (0/14) (p <0.01). However, this did not translate into a reduction in all-cause mortality in the overall population (vaccine group 89/502 (17.7%) vs. placebo group 80/504 (15.9%), p 0.4), notwithstanding pneumonia accounted for 32.5% of deaths in the control group.The results of the above-reported meta-analyses have been quoted to indicate PPV23 efficacy/lack of efficacy on different clinical outcomes. However, PPV23 was actually used in a limited number of the evaluated studies (7/22 studies included in the 2008 Cochrane review [
45
], and 8/22 included in the 2009 meta-analysis [44
]). The remaining studies considered vaccine valencies ranging from 2 to 17 serotypes, with a preference for the 14-valent vaccine. This must be kept under consideration when interpreting results on PPV23 efficacy.At present, there is little evidence that PPV23 protects against pneumococcal infections in the high-risk group of adults with HIV. Robust studies of PPV23 in HIV-infected persons are lacking [
49
]. Inefficacy of the vaccine in this group of patients could be attributed to the impaired production of capsule-specific IgG during the course of HIV infection. The only randomized control trial of PPV23 efficacy in HIV-infected patients showed potentially harmful outcomes in a Ugandan population [50
]. However, this study and most others in the field were undertaken at a time when the availability of highly active antiretroviral therapy was not widespread, making results difficult to evaluate in the current context of care.Attempts have been made to evaluate the cost-effectiveness of PPV23 vaccination of high-risk groups. In most studies evidence was found that PPV23 is relatively cost-effective and is particularly cost-saving when given to specific populations at high risk for pneumococcal disease such as the elderly. One such study determined the cost-effectiveness of pneumococcal vaccination of persons aged >65 years in preventing hospital admission for both invasive pneumococcal disease and pneumococcal pneumonia in five western European countries. Assuming a common incidence (50 cases per 100 000) and mortality rate (20-40%) for invasive disease, the cost-effectiveness ratios were <12 000 ecu (European currency units) per quality-adjusted life-year in all five countries [
51
]. It must be kept in mind that most studies on the topic were conducted before widespread pneumococcal conjugate vaccination among children. Given the beneficial ‘herd immunity’ effects observed in non-vaccinated adults (see later), the cost-effectiveness of PPV23 should probably be reassessed.Following vaccination with PPV23, pneumococcal serotype-specific IgG antibody titres decrease considerably by 5 years [
52
]. Given that the incidence of pneumococcal disease increases dramatically with age, revaccination of ageing patients is an attractive preventive strategy. However,
routine revaccination is not recommended because of concerns regarding potential immunological hyporesponsiveness with subsequent vaccine doses. Hyporesponsiveness is a phenomenon whereby the first dose of PPV23 may blunt the immune response to subsequent doses. This may be brought about by circulating antibodies derived from the first dose binding to vaccine antigen from the second dose, so preventing presentation to B cells [53
], through induction of memory suppressor T cells [54
], or depletion of memory B cells after polysaccharide vaccination [55
]. Although a second vaccination with PPV23 may generate lower antibodies compared with those generated by the first vaccination, it is difficult to judge whether this translates into a meaningful decrease in magnitude of clinical protection.The above limitations and doubts regarding PPV23 efficacy in populations most vulnerable to pneumococcal disease has stimulated investigation using alternative vaccine strategies. In addition to polysaccharide vaccines, so called ‘conjugate’ vaccines are now available. In these conjugate vaccines polysaccharide antigens are chemically conjugated to a highly immunogenic protein carrier (such as tetanus or diphtheria toxoid). From an immunological standpoint, conjugate vaccines direct processing of the protein carrier by polysaccharide-specific B cells and presentation of the resulting peptides to carrier-peptide-specific T cells in association with MHC class II molecules [
43
]. Therefore, a conjugate polysaccharide vaccine induces both a B-cell-dependent and a T-cell-dependent response and induces an anamnestic (memory) response to a booster dose of the vaccine [54
].Conjugate vaccines were initially applied to young children given that polysaccharide vaccines are poorly immunogenic in this population. A pneumococcal conjugate vaccine containing capsular polysaccharides from seven serotypes (PCV7) (see Table 1), designed for children younger than 2 years, was licensed in the USA in the year 2000. Implementation of the conjugated vaccine has tremendously decreased invasive pneumococcal diseases by vaccine serotypes in children [
55
]. Evidence exists that the elderly have indirectly benefited from the introduction of the pneumococcal conjugate vaccine in children [22
, 23
, 56
]. For example, in one study, IPD rates after PCV7 introduction compared with the prevaccination era were 32% lower for adults aged 20-39 years (7.6 cases/100 000 vs. 11.2/100 000, p <0.001), 8% lower for those aged 40-64 years (19.7/100 000 vs. 21.5/100 000, p 0.03), and 18% lower for those aged 65 years or more (49.5/100 000 vs. 60.1/100 000, p <0.001) [22
]. This indirect effect of vaccination is known as the herd effect or ‘herd immunity', defined as the indirect protection of unvaccinated persons, whereby an increase in the prevalence of vaccine immunity prevents circulation of infectious agents among unvaccinated susceptible populations [57
]. The herd effect has had a major impact in the eradication of smallpox [58
]. Specifically, because children are the main reservoir of S. pneumoniae (about 60% carrier rate), reduction in carrier rate in this population has beneficial effects on pneumococcal circulation that extend to non-vaccinated adult age groups. As a result of the reduced disease risk in adults following introduction of PCV7 among children, the magnitude of the potential benefit derived from PPV23 in older adults has also decreased, because of the lower risk of acquiring disease due to PCV7 strains.An additional observed benefit following the introduction of PCV7 was a reduction in the rates of antimicrobial-resistant S. pneumoniae invasive pneumococcal disease. One study detected a 49% reduction (from 16.4/100 000 pre-PCV7 to 8.4 cases/100 000 post-PCV7) of penicillin-non-susceptible pneumococcal strains [
59
]. In a different study, the introduction of PCV7 reduced the incidence of antibiotic resistance recorded in 1999 and 2002, from 40.8% to 26.4%, respectively for penicillin, from 34.9% to 9.4% for cephalosporin and from 29.5% to 18.1% for erythromycin [60
].As a result of these findings there has been interest in investigating the use of direct immunization of adult populations with conjugate vaccines. Given the shortcomings of PPV23 in groups at increased risk for pneumococcal disease such as the elderly and the immunosuppressed, studies have mainly involved these specific subpopulations. Possible advantages of conjugate vaccination in adult at-risk populations include higher protection against vaccine serotypes, and the possibility of prolonging the duration of protection by repeated vaccinations over time. Indeed, a trial comparing PPV23 with standard paediatric dose (0.5 mL) PCV7 in pneumococcal vaccine-naive patients aged >70 years found higher antibody titres following conjugate vaccine than after polysaccharide vaccination [
61
]. In a study on elderly patients who had previously been vaccinated with PPV23, revaccination with double-dose (1.0 mL) PCV7 was associated with higher post-vaccination antibody levels compared with revaccination with PPV23 [62
]. Studies in HIV-infected adults, patients with chronic obstructive pulmonary disease and adult stem cell transplant recipients have similarly shown PCV7 to have a superior immune response compared with PPV23 [63
, 64
, 65
].Although probably more immunogenic than PPV23, PCV7 contains a smaller number of serotypes compared with the polysaccharide vaccine. One strategy could be to first vaccinate susceptible adults with PCV7 and later also offer PPV23. The rationale is based on PCV7 inducing T-cell memory responses to the seven serotypes, which would be boosted by a subsequent dose of PPV23, along with the B-cell response induced by the polysaccharide vaccine to serotypes
not included in PCV7. There are concerns that if the order in which vaccines are administered is reversed, and PPV23 is administered first, then hyporesponsiveness may limit clinical efficacy. In the study by Jackson et al. [
62
], patients who received PCV7 followed by PPV23 showed an increase in antibody titres, conversely, in those who initially received PPV23, subsequent response to PCV7 was blunted.In the years following the introduction of PCV7 there has been an increase in the number of cases of IPD caused by serotypes not covered by the seven-valent pneumococcal conjugate vaccine, but present in PPV23 (particularly serotype 19A, which is associated with antibiotic resistance), and serotypes not present in either vaccine (such as 23A) [
66
]. Emergence of non-vaccinal serotypes as a cause of pneumococcal disease may offset the beneficial herd effect. In one study, although bacteraemic pneumococcal disease in adults caused by vaccine serotypes decreased by 29% per year, the rate of disease due to non-vaccine serotypes increased by 13% per year [67
]. Therefore, the relative reduction of vaccine serotypes appears to be greater than the increase of non-vaccine serotypes.New conjugate vaccines are now being evaluated for the vaccination of children and adults, a ten-valent (PCV10), which has been licensed in over 30 countries, and a 13-valent (PCV13) vaccine (see Table 1). The increased serotype coverage of these vaccines, particularly PCV13, may expand the clinical benefits of conjugate vaccines in adult populations at risk for pneumococcal disease. A large Dutch randomized controlled trial designed to test the protective efficacy of PCV13 towards pneumococcal pneumonia is currently underway, and will enrol over 85 000 patients aged over 65 years [
68
]. A simulation study on the cost-effectiveness of the three conjugate vaccines showed that the introduction of PCV10 vs. PCV7 reduces by $32 131.51 the cost for quality-adjusted life-years utility per time and PCV13 vs. PCV10 by $34 790.19 for quality-adjusted life-years gained, taking into account both direct and indirect (herd) effects [69
]. Some authors suggest that, given the expected indirect herd immunity beneficial effects in adult at-risk populations following widespread paediatric newer conjugate vaccine (e.g. PCV13) immunization, the need for direct vaccination of adult populations may be diminished [70
]. However, further data are needed to confirm this hypothesis. A recent randomized, double blind trial evaluated concomitant PCV13 and trivalent influenza vaccination in adults aged ≥65 years, and found acceptable immunogenicity and safety compared with either agent alone. The possibility of administering both vaccines concomitantly is an important way to facilitate immunization of high-risk populations [71
].Lastly, studies are underway for the development of pneumococcal vaccines based on protein components such as pneumolysin that are antigenically conserved across different serotypes and may therefore provide protection against most serotypes [
72
].Conclusions
The aging population aging and the epidemic in chronic illness will lead to a sharp increase of pneumococcal infection rates and costs. Prevention of pneumococcal infections by vaccination may be a valid strategy to reduce the burden of diseases, antibiotics resistance and costs. Vaccination strategies based on the use of more effective vaccines, in particular the PCV13 vaccine, are expected to have a substantial public-health impact on infectious disease and health services costs, reducing the burden of pneumococcal infection.
Conflict of interests
The authors have no conflict of interest to declare.
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Article Info
Publication History
Accepted:
February 2,
2012
Received in revised form:
January 2,
2012
Received:
November 17,
2011
Footnotes
Editor: M. Paul
Identification
Copyright
© 2012 European Society of Clinical Infectious Diseases. Published by Elsevier Inc.
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