impact of conjugate pneumococcal vaccines on the changing epidemiology of pneumococcal infections

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Streptococcus pneumoniae-related infections have a major global impact on healthcare, especially in the developing world, and are considered the number one vaccine-preventable cause of death in children [1]. These bacteria cause a variety of illnesses that include invasive pneumococcal diseases (IPDs) such as bacteremia, meningitis and bacteremic pneumonia. Furthermore, they are a common cause of mucosal infections such as otitis media, sinusitis, mastoiditis and non-bacteremic pneumonia (Figure 1) [2]. Between 0.7–1 million deaths were attributed to pneumo-coccal disease among children under 5 years of age in developing countries in 2005 [3,4]. More than 90 pneumococcal serotypes have been iden-tified and grouped among 46 serogroups based on differences in the antigenic characteristics of the capsular polysaccharide [5]. After 10 years of use, the polysaccharide–protein 7-valent pneumococcal conjugate vaccine (PCV-7) has had a tremendous impact in the decline of IPD, mucosal infections, the decrease of antimicro-bial-resistant strains, and has also produced a herd immunity effect. However, non-PCV-7 serotypes such as serotypes 1, 3, 5, 7F and 19A were important in different regions of the

world or became important after various years of PCV-7 usage. New-generation vaccines that include these emerging serotypes, while main-taining protection against the PCV-7 serotypes, have been recently approved based on immuno-genicity and preliminary safety data established by different regulatory agencies. The effective-ness of these new vaccines should be followed closely over the coming years.

Pneumococcal conjugate vaccine & its developmentIn 1977, the f irst capsular polysaccharide pneumo coccal vaccine was licensed in the USA for individuals older than 2 years of age at high risk for pneumococcal disease [6]. In total, two decades later, the first PCV-7 completed the required clinical trials and was introduced as part of the national immunization program of various countries. PCV-7 contains antigens of the seven S. pneumoniae serotypes most com-monly found in the developed world. These seven serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) are conjugated with a nontoxic CRM

197 diphthe-

ria protein and are associated with 65–80% of IPD affecting children in Western industrialized

Tirdad T Zangeneh1, Gio Baracco1 and Jaffar A Al-Tawfiq†2

1Division of Infectious Diseases, University of Miami Miller School of Medicine and the Miami Veterans Affairs Healthcare System, Miami, FL, USA 2Aramco Services Organization, Saudi Aramco, Saudi Arabia †Author for correspondence:Tel.: +96 638 773 524 Fax: +96 638 773 790 [email protected]; [email protected]

Streptococcus pneumoniae-related infections have a major global impact on healthcare, especially in the developing world, and are considered the number one vaccine-preventable cause of death in children. There are more than 90 pneumococcal serotypes and 46 serogroups. The first capsular polysaccharide pneumococcal vaccine was licensed in the USA in 1977 for individuals older than 2 years of age at high risk for pneumococcal disease. Two decades later, the first 7-valent pneumococcal polysaccharide–protein conjugate vaccine completed the required clinical trials and was introduced as part of the national immunization program of various countries. New-generation vaccines that include emerging serotypes, while maintaining protection against the 7-valent pneumococcal serotypes, have recently been approved. With the addition of these serotypes, the majority of potential pneumococcal serotypes causing invasive disease in most parts of the world could be covered.

Keywords: pneumococcal vaccine • respiratory infection • vaccination

Impact of conjugate pneumococcal vaccines on the changing epidemiology of pneumococcal infectionsExpert Rev. Vaccines 10(3), 345–353 (2011)

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countries [7]. In the pivotal clinical trial performed at Kaiser Permanente (CA, USA), PCV-7 proved to be highly effective against IPD and less effective against the prevention of otitis media [8]. Another pivotal study was carried out in Finland where a more detailed evaluation of the efficacy of PCV-7 was analyzed for the prevention of otitis media in culture-proven cases [9]. In this study, an overall 6% reduction in the cases of otitis media was demonstrated among those children vaccinated with PCV-7 and a 54% reduction of otitis media episodes produced by PCV-7 sero-types was observed. Following the results of these studies, PCV-7 was approved by the US FDA in February 2000 and later released into the European market in 2002 [10]. By May 2009, PCV-7 had been introduced into the national immunization program of 35 countries [4]. In addition, the first Global Alliance for Vaccines and Immunization-eligible country, Rwanda, introduced PCV-7 into its national immunization program [11].

On 24 February 2010, the 13-valent pneumococcal conjugate vaccine (PCV-13) was licensed by the FDA for use among chil-dren aged 6 weeks to 71 months for the prevention of IPD and otitis media [12]. PCV-13 is based on the foundation of PCV-7 and introduces an additional six new serotypes (1, 3, 5, 6A, 7F and 19A). It uses the same protein carrier (CRM

197) as PCV-7 [13].

These new serotypes were introduced into PCV-13 because of various factors. PCV-7 cross-protection against serotype 6A, although significant, was partial and many studies demonstrated that following vaccination with PCV-7, nasopharyngeal carriage of 6A was still present as well as invasive infection in children due to this serotype. In the case of serotype 19A, a major increase of a multidrug-resistant 19A clone has been observed in many coun-tries, particularly in children less than 2 years of age and in adults older than 65 years of age [14,15]. Serotypes 1 and 5 are prevalent

in many developing countries such as in Asia, Africa and Latin America, and these serotypes are found commonly in children with complicated lower respiratory tract infections (pneumonia and pleural effu-sion) as well as in bacteremic children [16]. In the case of serotype 3, this is problem-atic because of the larger capsule, which has been found in several studies as the most common non-PCV-7 in the middle ear fluid of children with otitis media and as a cause of complicated lower respiratory tract infection with empyema [17]. The new PCV-13 vaccine may increase serotype cov-erage in many regions of the world, target-ing 80–92% of serotypes producing IPD in children younger than 5 years of age worldwide [101].

An analysis led by the CDC in 2007 found that among 427 IPD cases with known sero-types in children aged less than 5 years of age in the USA, a total of 274 (64%) were caused by serotypes contained in PCV-13. This study estimated that 2900 of the

approximately 4600 cases of IPD that occur yearly in children less than 5 years of age in the USA were caused by serotypes included in PCV-13 [18]. The Advisory Committee on Immunization Practices (ACIP) recommends PCV-13 for all children aged 2–59 months. ACIP also recommends PCV-13 for children aged 60–71 months with underlying medical conditions that increase their risk for pneumococcal disease or complications [12].

The other new conjugate S. pneumoniae vaccine contains ten pneumococcal serotypes (PCV-7 serotypes plus serotypes 1, 5 and 7F) and contains protein D as a carrier for eight of the ten serotypes. Protein D is a glycoprotein found among nontypable Haemophilus influenzae strains and one of the claims of this vaccine is that it offers protection against nontypable H. influenzae infec-tions, particularly otitis media [19]. The serotypes 18C and 19F use tetanus toxoid and diphtheria toxoid as carriers, respectively [20].

Pharmacology & immunogenicity of the vaccinesThe PCVs, unlike the 23-valent pneumococcal polysaccharide vaccine, are immunogenic in children less than 2 years of age [10]. In the USA, approval of PCV-7 was based on a randomized con-trolled study in which PCV-7 administered to 38,000 infants at 2, 4, 6 and 12–15 months of age was 97.4% (95% CI: 82.7–99.9%) efficacious in preventing IPD caused by vaccine serotypes [8]. Other studies evaluating the antibody response to pneumococcal antigens reported statistically significant increases in geometric mean concentrations for all seven serotypes 1 month after the third dose of PCV-7 [21]. In those studies, from 98.3 (serotypes 9V and 23F) to 100% (serotypes 4, 6B, 14, 18C and 19F) of subjects achieved appropriate pneumococcal antibody concentrations [21]. A review of several studies looking at immunogenicity after three doses of PCV-7 have reported pneumococcal antibodies above

Death

Meningitis

Bacteremia

Pneumonia

Acute otitis media

Figure 1. Pneumococcal clinical syndromes.Taken from [68].

Zangeneh, Baracco & Al-Tawfiq

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the cutoff level (at least 0.35 µg/ml) being achieved among 82–100% of participants for all vaccine serotypes covered, irrespec-tive of whether the vaccine was adminis-tered at 2, 3 and 4 months or at 2, 4 and 6 months (Table 1) [10]. PCV-7 is sufficiently immunogenic after administration of a four-dose vaccination schedule in infants [10], and therefore the vaccine is usually administered along with other childhood vaccines in children of 2–15 months of age [22].

Although PCV-7 provides some protec-tion against disease caused by serotype 6A, this protection does not reach the same extent of that seen against types actually contained in the vaccine [23]. However, PCV-7 provides no protection against disease caused by serotype 19A [24]. The immuno genicity of PCV-7 has recently raised interest for its use among special populations. In a recent multicenter obser-vational study, premature infants with very low birth weight enrolled from the National Institute of Child Health and Human Development Neonatal Research Network centers had similar antibody responses to most PCV-7 vaccine serotypes when compared with larger premature infants [25].

Another area of interest has been the impact of PCV-7 among HIV-infected children. In a South African vaccine efficacy trial in HIV-infected children, the attributable rate reduction in clini-cal lower respiratory infections was almost 15-times greater for HIV-infected children than for uninfected children. At 6-year follow-up, the vaccine-attributable rate reduction in IPD was 59-times higher for HIV-infected children than for uninfected children [26]. More recently, a double-blind, randomized, placebo-controlled clinical efficacy trial of PCV-7 among 496 (88% HIV-seropositive) Malawian adolescents and adults who had recovered from documented IPD was conducted. In this secondary prophy-laxis trial, a dose of PCV-7 prevented 74% of recurrent episodes of IPD caused by vaccine serotypes or serotype 6A in patients with HIV infection with the efficacy being highest during the first 12 months after vaccination [27].

The clinical evaluation and licensure of new PCVs are based on the WHO immunogenicity guidelines. These guidelines refer to the demonstration of noninferiority in a head-to-head comparison with PCV-7. The guidelines call for the calculation of the proportion of subjects developing antibody concentra-tions above a defined threshold (0.35 µg/ml) at 4 weeks follow-ing a primary series of vaccination or a 0.20 µg/ml threshold using the 22F adsorption technique [28,29]. In addition, there should be a demonstration of functional antibodies measured with opsono phagocytic antibodies (OPAs) after three doses and a test of immune memory, such as avidity or the ability to induce a booster response. Based on these guidelines, OPA titers were available from two studies of the effectiveness of

PCV-13 and showed that antibody concentrations in the range of 0.20–0.35 mg/ml correlated best with an OPA titer of 1:8 and with protective efficacy [29].

Previous immunogenicity studies have suggested that anti-body responses from PCV-7 regimens consisting of two doses in the primary series are less immunogenic for two of the vac-cine serotypes (6B and 23F) in comparison to a three-dose regi-men [30,31]; therefore, a study looking at the rates of lower respira-tory tract disease among children who had received two versus three PCV-7 doses in the primary series was undertaken [32]. The authors’ findings supported the use of a three-dose primary PCV-7 series, arguing that this regimen was more effective in preventing lower respiratory tract-related morbidity during the first year of life, although this difference disappeared after the booster dose when using either 2+1 or 3+1 vaccine regimens. They also noted that, while the early success of the two-dose plus booster regimen recommended in the UK, Quebec and Norway has been demonstrated to prevent IPD, this may differ in the developing world where booster doses are not uniformly utilized and poor nutrition and lower immunity has an impact on the pathogenesis of disease.

The immunogenicity of 10-valent pneumococcal non-typable H. influenzae protein D-conjugate vaccine (PHiD-CV; GlaxoSmithKline Biologicals, Rixensart, Belgium) containing polysaccharides from pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F was also compared against PCV-7, showing that the vaccine induced ELISA and functional OPAs for all vaccine serotypes after primary vaccination and overall was noninferior to PCV-7 [33]. Several other studies published during the same period provided a comprehensive evaluation of

Table 1. Comparison of the percentage of subjects reaching the threshold of 0.35 µg/ml using PCV-13, PCV-7 and PHiD–CV, 1 month after the primary dose series.

Serotype PCV-13 (%) PCV-7 (%) PHiD-CV (%)

4 98.2 98.2 94.8

6B 77.5 87.1 54.8

9V 98.6 96.4 94.0

14 98.9 97.5 99.0

18C 97.2 98.6 90.7

19F 95.8 96 89.1

23F 88.7 89.5 66.6

1 96.1 1.4 90.2

3 98.2 6.3 -

5 93.0 31.6 95.5

6A 91.9 31.6 9.7†

7F 98.6 4.0 97.4

19A 99.3 79.2 8.2†

†Cross-reactive serotypes.PCV-7: 7-valent pneumococcal conjugate vaccine; PCV-13: 13-valent pneumococcal conjugate vaccine; PHiD-CV: 10-valent pneumococcal nontypable Haemophilus influenzae protein D-conjugate vaccine.Table modified from [13] with additional data from [71,72,33].

Impact of conjugate pneumococcal vaccines on pneumococcal infections

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the PHiD-CV vaccine and the observed differences in immuno-genicity profiles between the two vaccines appeared to be similar and without major differences in IPD protection [34].

Immunogenicity studies comparing PCV-13 to PCV-7 using the WHO-confirmed noninferiority criteria indicated that PCV-13 is immunogenic and noninferior to PCV-7 against the PCV-7 sero-types and immunogenic against the additional six serotypes [13]. Newer studies comparing both PCV-7 and PCV-13 have shown both pneumococcal vaccines are highly immunogenic for all of their serotypes represented and the immune response to the seven common serotypes evoked by PCV-13 after the toddler dose was not demonstrated to be inferior to that evoked by PCV-7. However, it has also been observed that vaccination with the primary series of PCV-13 achieved a lower immunogenicity for serotypes 6B and 23F [35].

Emergence of nonvaccine serotypes & serotype replacement following the introduction of the conjugated vaccineSerotype replacement has been described as taking one of two forms: either an increase in prevalence of types already present in the population, or the appearance and spread of types previously absent from the population owing to their inability to compete with the vaccine type(s) [36]. Some experts have argued that serotype replacement is a complex phenomenon and that serotype distribu-tion and disease that is preventable by vaccine depends on both time and geography. Thus, the increases in the nonvaccine sero-types may be due to the introduction of new clones or expansion of existing clones, or possibly due to capsular switch of resident bacte-ria [37]. Other authors have raised the argument that the prominent increases in non-PCV-7 serotypes among some populations are not due to serotype replacement but due to other mechanisms such as the differences in the frequency of comorbid conditions, immuno-suppression, antibiotic use, serotype distributions, or environmental conditions contributing to these changes [38].

Whatever the mechanism, following the introduction of PCV-7, several studies have shown that use of PCV-7 has led to the resurgence of serotypes not covered in the vaccine [39,40]. Across the USA as a whole, serotypes isolated from blood and other sterile sites and nonsterile sites represented by the PCV-7 vaccine decreased in prevalence from 65.5% in 2000–2001 to 34.7% in 2002–2003 and to 27.0% in 2003–2004 [41]. Although during the first year the proportion of Streptococcus pneumoniae with PCV-7-covered serotypes was higher in isolates cultured from blood compared with other sites; by 2004, this pattern was no longer documented. The use of the PCV-7 vaccine has been reported to reduce infections caused by vaccine-covered serotypes but at the same time has led to an increase in infections caused by nonvaccine-related serotypes including serotype 6A and 19A [1]. The most common IPD isolates since PCV-7 introduction are serotypes 1, 19A, 3, 6A and 7F [42]. Nonvaccine S. pneumoniae serotypes have replaced the seven vaccine serotypes among chil-dren less than 5 years of age, with the greatest increase seen with serotype 19A. In addition, other serotypes (11, 15, 33 and 35) more than doubled after the introduction of the vaccine [43].

Although an increase in nonvaccine serotypes has been described after the introduction of the PCV in Europe, it has been argued that even in the absence of immunization, increases in specific serotypes may occur that are not related to the replace-ment phenomenon but are due to simple capsular switching [2]. Capsular switching is different from serotype replacement. It reflects the agility of pneumococcus, whereby as part of a quorum-sensing mechanism, it can acquire new traits in a process called transformation. Through this process, S. pneumoniae acquires a cassette of DNA that encodes production of a serotypically different capsule [44]. Concern has been raised regarding the role of capsular switching in the emergence of non-PCV-7 serotypes, particularly 19A, where it has been hypothesized that there is the possibility that 19F clones were co-transformed to the 19A serotype, confer-ring increased penicillin resistance [1]. This is exemplified in the two studies discussed in the following paragraphs.

An increase in serotype 19A-associated IPD has been reported among Korean children before the introduction of PCV-7. In this study, the overall proportion of serotype 19A isolates increased from 0% in 1991 to 26% in 2003 but with a decrease in the 19F isolates during the same time period, and the researchers demon-strated that multidrug-resistant isolates were responsible for the increase in serotype 19A before the introduction of PCV-7 [45].

In another study by Dagan et al., the authors described an increase in the frequency of 19A-related acute otitis media (AOM) among Bedouin children in Southern Israel who were exposed to overcrowding and high antibiotic use prior to the introduction of PCV-7. Multidrug resistance increased and was associated with the introduction and proliferation of two multidrug-resistant clones that had not been previously associated with multidrug resistance and was associated with the increased usage of azithromycin and oral cephalosporins [46].

Reports of an increased prevalence of multidrug-resistant, non-vaccine serotypes caused by the selective pressure of the conjugate vaccine on serotypes led to new studies looking at the changes in S. pneumoniae antimicrobial resistance in the USA before and after the introduction of the PCV-7. Mathematical models of sero-type replacement had predicted a rebound in resistance prevalence due to the continued antimicrobial consumption pressure [47]. Another study evaluated the genetic characteristics and penicillin nonsusceptibility of non-PCV-7 serotypes and found increased proportions of specific penicillin-nonsusceptible clones among serotypes 15A, 23A, 35B and 6C. As a result they argued that this had indicated a basic change of population structure within the individual serotypes rather than a recent capsular switching event [48].

Changes in the epidemiology of IPD with widespread vaccinationAccording to Whitney et al., the rate of IPD in the USA decreased from an average of 24.3 cases per 100,000 persons in 1998–1999 to 17.3 per 100,000 in 2001 [49]. The largest decline occurred among children less than 2 years of age, in whom the rate of dis-ease was 69% lower in 2001 than at baseline [49]. Disease rates also decreased among adults in comparison with baseline rates, whereas


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in 2001 disease rates were 32% lower for adults 20–39 years of age, 8% lower for those 40–64 years of age, and 18% lower for those 65 years and over [49]. A more recent study confirms this trend. Data from Active Bacterial Core surveillance indicate that, by 2007, the overall incidence rate of IPD among persons of all ages had decreased by 45% (from 24.4 to 13.5 per 100,000 population) compared with 1998–1999, before PCV-7 was introduced [102]. In this study, the rate of IPD decreased by 76% in children less than 5 years of age, and by 40, 18 and 37% among individuals aged 18–49, 50–64 and ≥65 years, respectively. The major reason for such decline is the reductions of 94% in cases of infection with serotypes covered in PCV-7. However, these reductions were par-tially offset by the increases in nonvaccine serotypes, including the predominant serotype 19A [38].

Pilishvili et al. also reported significant increases in the inci-dence of meningitis and invasive pneumonia caused by nonvac-cine serotypes, but not in the frequency of primary bacteremia [38]. This had been previously speculated to relate to changes in the circulating serotypes and their ability to cause different clinical syndromes resulting in increased hospitalizations. However, the researchers highlighted the presence of comorbid conditions, and not infection with nonvaccine serotypes, as the likely reason for the greater severity of nonvaccine serotype IPD cases [38].

Efficacy of pneumococcal conjugate vaccine in the prevention of mucosal pneumococcal infections (AOM, sinusitis & pneumonia) Acute otitis media is the most common infection associated with colonization of the upper respiratory tract by pneumo-coccus and the most common infection for which antibiotics are prescribed for children in the USA [50]. The most common pneumococcal serotypes causing AOM in children less than 18 years of age are 3, 6A, 6B, 9V, 14, 19A, 19F and 23F [51]. The widespread introduction of PCV-7 has had a significant impact on the frequency of AOM caused by pneumococcus. In the USA, physician visits for AOM decreased by 20% in children less than 2 years of age, the frequency of persistent and recur-rent AOM was reported to be 24% lower, and the frequency of AOM leading to tympano stomy tube insertion was decreased by 24–39% [52,53]. In another study, Zhou et al. compared the rates of ambulatory visits and antibiotic prescriptions related to AOM treatment between 2004 and the 1997–1999 periods [54]. The authors described a 42.7% reduction in AOM-related visits and 41.9% reduction in treatment-related prescriptions. The authors attributed the use of PCV-7 to significant reduc-tions in the burden of AOM and subsequent savings in medical care costs [54].

In Canada, after using a different vaccine schedule (two doses during the first year followed by a booster after 12 months of age) claims for AOM decreased by 13.2% [55]. Specifically, there has been a significant decrease in vaccine serotypes and an increase in nonvaccine serotypes 3, 6A and 19A [52]. In order to evalu-ate the dynamics of AOM caused by serotype 19A prior to the introduction of PCV-7, a group of researchers in Southern Israel studied AOM among children during 1999–2006. They found

that infections caused by serotype 19A increased by 63.1% from 1999–2001 to 2004–2006, with an increase in multidrug resis-tance, and concluded that the introduction and proliferation of multidrug-resistant seroytype 19A occurred before the introduction of PCV-7 [46].

There is less data available regarding the effect of the introduc-tion of PCV-7 on the incidence of sinusitis in children. One par-ticular study, which examined nasopharyngeal cultures among children with sinusitis, reported a decrease from 43 to 25% in the prevalence of S. pneumoniae from 1996–2000 to 2001–2005 [56]. In addition, the researchers observed that serotype 19A had become the most common serotype isolated, accounting for over 50% of the isolates from chronic or recurrent pneumo-coccal sinusitis – the majority of them being nonsusceptible to penicillin [57].

In the USA, a 39% decrease in admission rates for pneumonia in children aged less than 2 years had been reported 4 years after the introduction of PCV-7 infant immunization programs [58]. As a result, PCV-7 was introduced to the childhood national immu-nization program in England in September 2006 [59]. Following this introduction, a population-based time-trend analysis of bacterial pneumonia-associated admissions among children less than 15 years of age demonstrated a decrease of 19 and 22%, respectively, between 2006 and 2008 [59].

A study was conducted recently to examine the public health and economic impact of pneumococcal vaccination policies in the context of influenza epidemics/pandemics and showed that early PCV-7 vaccinations were highly effective and cost saving [60]. These authors have argued that there is a strong rationale for considering pneumococcal vaccination in the context of influ-enza since there is an increased risk of influenza and pneumo-coccal disease coinfection during a pandemic. Other experts have reviewed the data on the impact of the 1918 influenza pandemic and have argued that the high mortality was partly attributable to pneumococcal infections and that pneumococcal vaccination for children and adults is an important part of pandemic influenza preparedness [61].

Antimicrobial resistance in pneumococcal disease after the introduction of the conjugate vaccineIn 1967, the first cases of S. pneumoniae resistance to penicil-lin were reported in Australia, soon followed by New Guinea in 1974, South Africa in 1977 and Spain in 1979. Antibiotic-resistant pneumococcus then spread globally. The predominant resistant serotypes during the 1980–1990 period were 6A, 6B, 9V, 14, 15A, 19A, 19F and 23F [62]. During the mid 1990s the incidence of penicillin-nonsusceptible IPD continued to rise. The US CDC reported that 24% of the strains were nonsus-ceptible to penicillin in 1998: serotypes 6B, 9V, 14, 19F and 23F, all of which are included in PCV-7, accounted for 78% of these strains [63].

The decreased carriage of PCV-7-serotype strains provided a biological niche for pre-existing nonvaccine serotypes, including penicillin-nonsusceptible strains, in the post-PCV-7 period [48]. Soon after the introduction of PCV-7, and in direct relation to


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vaccine penetration, the incidence of IPD and the rate of anti-biotic resistance among vaccine serotypes declined significantly in the USA [64]. The rate of penicillin-nonsusceptible invasive disease among children under 2 years of age fell by 81% and rates among children 2–4 years of age were 60% lower in 2004 than at baseline in 1999 [64]. However, soon after this early decline in resistance, an increase in antimicrobial-resistant nonvaccine serotypes was observed. This included resistance to penicillin, macrolides, cotrimoxazole and amoxicillin–clavulanate [41].

In New York City, NY, USA, the proportion of penicillin-nonsusceptible strains increased from 27% prior to vaccine availability to 49%. While it was noted that the rate of IPD caused by these nonsusceptible strains did not change when researchers compared the 1995–1999 period to the 2002–2006 period, the strains causing IPD in the post-PCV-7 vaccine era were significantly more likely to be penicillin nonsuscep-tible [63]. The CDCs Active Bacterial Core surveillance system reported that, in 2007, 26% of pneumococcal isolates from patients with IPD were penicillin nonsusceptible [102]. Over half of these isolates belonged to serotype 19A, and other non-PCV-7 serotypes accounted for an additional 40% [48]. A prospective cohort study among children receiving PCV-7 between 2003 and 2006 in New York showed that strain 19A had emerged as an otopathogen resistant to all FDA-approved antibiotics for the treatment of AOM in children living in the USA [52]. This then raised the possibility that there is a compensatory increase in carriage of drug-resistant pneumococcal disease after vac-cination [65]. Some have described a process in which, as the vaccine serotypes became less frequent, many more susceptible isolates are lost than multidrug-resistant isolates, leading to greater prevalence of these multidrug-resistant isolates despite a decrease in the total number of isolates [47].

This same pattern has not been seen throughout the globe. For instance, low levels of antibiotic resistance have been reported in Denmark and other Scandinavian countries exposed to limited antibiotic selective pressure and conjugate pneumococcal vaccina-tion, where it has been estimated that the proportion of isolates with decreased susceptibility to penicillin have remained at 2–4% since 1994 [66].

Impact of child immunization on the epidemiology of pneumococcal disease in adultsThe idea that vaccination of a particular population can protect other populations through herd immunity is an attractive idea for the use of vaccines in general. During the efficacy clini-cal trial with PCV-7, an indirect protection was not initially detected, but this was promptly detected when the vaccine was introduced into the national immunization programs of differ-ent countries and it was estimated that the vaccination of one child would result in the protection of 2.2 individuals. Reports have indicated that the use of the pneumococcal protein conju-gate vaccine among children impacted the total number of IPD cases and resulted in a 38% decrease in the rate of IPD among nonvaccinated elderly adults through herd immunity [67]. The impact of the vaccine on herd immunity has been attributed to

the decrease in nasopharyngeal carriage of vaccine serotypes, leading to a reduction in disease transmission. This has been seen with the introduction of the PCV in North America; although it has not been confirmed in Europe and South Africa where different sociological conditions may impact transmission patterns [68]. Pilishvili et al. found that 7 years after the intro-duction of PCV-7 immunization in children, there were large reductions in PCV-7-type IPD rates among adults [38]. These, however, remained elevated compared with rates in children. In this particular study, the overall IPD incidence in 2007 was reported to be 45% lower for all age groups and 76% lower for children less than 5 years of age compared with pre-vaccine baseline incidence. This raised the possibility that the effects of herd immunity may be partially offset by the increase in nonvaccine-covered serotypes. This was demonstrated by data showing that, among adults aged ≥65 years, IPD rates caused by serotypes 6A/C increased by 70% and the rate of IPD caused by serotype 23A increased from 0.4 to 2.2 cases per 100,000 population [38].

Expert commentaryStreptococcus pneumoniae-related infections have a major global impact on healthcare worldwide. Annually, between 0.7 and 1 million deaths are attributed to pneumococcal disease among children under the age of five in developing countries. The introduction of PCV-7 resulted in a significant decline of IPD. Subsequently, the introduction of the conjugated pneumococcal vaccine caused further reduction in the disease burden, although there is a growing concern regarding serotype replacement and disease caused by pneumococcal serotypes not included in the current vaccine formulations. The available evidence suggests that the benefit from introducing the vaccine far outweighs the risk of such a concern.

Five-year viewThe epidemiology of pneumococcal carriage and infection is highly dynamic. The widespread use of PCV-7 has seen its effi-cacy tampered by the resurgence of non-PCV-7 serotypes, some of which have high rates of antimicrobial resistance. The intro-duction of PCV-10 and PCV-13 attempt to overcome this phe-nomenon, and time and continued epidemiological monitoring will tell how successful they will be.

Several studies are ongoing that attempt to measure the effi-cacy of pneumococcal vaccination in special populations. A pla-cebo-controlled trial of PCV-13 entitled ‘Community Acquired Pneumonia Immunization Trial in Adults’ is being performed in The Netherlands to establish the efficacy of the vaccine in the prevention of a first episode of vaccine-serotype-specific pneumococcal community-acquired pneumonia in 85,000 com-munity-dwelling adults aged 65 years and older [69]. However, results of this study will not be available until 2012.

The incidence of IPD in adults with certain hematological and solid-organ malignancies is significantly greater than the overall adult population [70]. In a recent study, 35% of IPD cases in patients with malignancies were caused by serotypes in


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Key issues

• Streptococcus pneumoniae-related infections have a major global impact on healthcare.

• Between 0.7–1 million deaths were attributed to pneumococcal disease among children under 5 years of age in developing countries in 2005.

• The 7-valent pneumococcal conjugate vaccine (PCV-7) had a tremendous impact in the decline of invasive pneumococcal disease.

• The non-PCV-7 serotypes such as serotypes 1, 3, 5 7F and 19A were important in different regions of the world or became important after various years of PCV-7 usage.

• New-generation vaccines have been developed to address emerging serotype coverage, while maintaining protection against the PCV-7 serotypes.

• Serotype replacement may take one of two forms: an increase in prevalence of types already present in the population, or the appearance and spread of types previously absent from the population.

• The effects of herd immunity may be partially offset by the increase in nonvaccine-covered serotypes.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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• Althoughanolderstudy,thiswasoneofthefirstpaperspublishedaftertheuseofthepneumococcalpolysaccharidevaccineandraisedtheissueofresearchneededtosupportwidespreadpneumococcalvaccination.

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PCV-7, 37% of cases were caused by serotypes in PCV-10, and 57% were caused by serotypes in PCV-13. As a result, it has been proposed that the use of PCV-13 in this high-risk population, as well as in children, may confer beneficial protective effects against IPD [70]. Novel vaccines under study explore different vehicles, antigens and adjuvants, attempting to find a broadly immunogenic, safe and inexpensive pneumococcal vaccine.

Financial & competing interests disclosureThe authors have no relevant affiliations 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.


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impact of conjugate pneumococcal vaccines on the changing epidemiology of pneumococcal infections

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