Streptococcus pneumoniae is a leading cause of morbidity and mortality worldwide, resulting in an estimated 826,000 deaths globally each year in children 1 month to 5 years of age.1S. pneumoniae is a Gram-positive diplococci that is characterized by a thick polysaccharide capsule that shields the bacterium from the human immune system. Although more than 90 immunogenetically distinct serotypes exist and the prevalence of serotypes varies regionally, only 10 serotypes cause more than two-thirds of disease globally.2
Nasopharyngeal (NP) colonization with S. pneumoniae is common in young children and is generally asymptomatic.3Only a fraction of those colonized develop disease. The triggers that result in pneumococcal colonization or disease are largely unidentified; however, risk factors include low socioeconomic status, crowding, malnutrition, lack of breast feeding and recent viral infections.3 The risk of developing pneumococcal disease is dramatically increased in immunocompromised persons, such as those with active HIV infections or sickle cell disease. Pneumococcal strains are not equally pathogenic; strains can be common NP colonizers but rarely result in disease.3 For serotypes that commonly cause disease, nasal carriers also act as reservoirs and vectors that transmit the bacteria to noninfected individuals.4
S. pneumoniae causes a variety of diseases including sinusitis, acute otitis media (AOM), pneumonia, bacteremia and meningitis. The most common clinical manifestation of S. pneumoniae is AOM, with pneumococci isolated in 25–50% of middle ear aspirates.5 Although pneumococcal AOM causes few deaths, it is responsible for a large burden of disease. In the United States, AOM is the leading cause of pediatric office visits, resulting in 25 million visits each year, and is the leading cause of antibiotic prescription for infections.5 Furthermore, otitis media, especially repeated occurrence, can lead to hearing loss.
S. pneumoniae is a leading cause of community-acquired pneumonia, causing an estimated 13.8 million cases of pneumonia each year globally, and accounts for 90% of all deaths caused by pneumococcus.1 The majority of community-acquired pneumococcal pneumonia cases are not overtly bacteremic, limiting the sensitivity of blood cultures in determining etiology. Invasive pneumococcal disease (IPD), disease where pneumococci are identified in normally sterile fluid, includes bacteremic pneumonia, sepsis and meningitis. Nonpneumonia IPD such as sepsis and meningitis, account for only 10% of deaths caused by pneumococcus,1 but the severity of the disease is greater; pneumococcal meningitis has a case fatality rate of approximately 30% and can cause neurologic sequelae in 28–63% of survivors.6,7 By comparison, mortality rates for pneumonia range from 2% to 11%.1 Incidence and case fatality rates for pneumonia and other invasive disease are higher in lower income countries, with 61% of all pneumococcal deaths occurring in 10 low and middle income countries.1
Development of pneumococcal vaccines has been complicated by the diversity and limited immunogenicity of the polysaccharide capsule of S. pneumoniae. Before the year 2000, the only pneumococcal vaccine available commercially was a 23-valent purified capsular polysaccharide vaccine. The vaccine has been shown to be effective against IPD in adults, but antibody response in children younger than 2 years of age is poor.7 Since the mid-1990s, several pneumococcal conjugate vaccines (PCV) have been developed by chemically bonding pneumococcal capsular polysaccharides to a carrier protein. This alteration helps infants’ immature immune system better respond to the vaccine and enhances the T cell–dependent immune response, which produces elevated titers of high avidity immunoglobulins and a strong memory response.8 Thus, repeated immunization with the vaccine induces an enhanced immunologic response, resulting in greater protection.
Three PCVs are currently available on the market: Pfizer’s (formerly Wyeth Lederle Vaccines) 7-valent conjugate pneumococcal vaccine Prevnar (PCV-7) and 13-valent product Prevnar 13 (PCV-13), first licensed in 2000 and 2009, respectively, and GlaxoSmithKline’s 10-valent product, Synflorix (PCV-10), first licensed in 2008.2 PCV-7 contains polysaccharides from the 7 most common invasive pneumococcal strains in North America, serotypes 4, 6B, 9V, 14, 18C, 19F and 23F, conjugated to a nontoxic diphtheria-toxin analog (CRM197).7 The development of PCV-13 used PCV-7 as a base, but included serotypes 1, 3, 5, 6A, 7F and 19A conjugated to CRM197 in addition to the serotypes present in PCV-7. A 9-valent PCV (PCV-9), a derivative of PCV-7 and precursor to PCV-13, which included serotypes 1 and 5 in addition to PCV-7’s serotypes, was tested in clinical trials in low and middle income countries, but was never licensed for routine use. PCV-10 was developed separately, and the polysaccharides it contains are conjugated to proteins from either diphtheria, tetanus, or nontypeable Haemophilus influenzae, a major cause of AOM,5 depending on the serotype. It contains polysaccharides from serotypes 1, 5 and 7F in addition to those present in PCV-7. It was originally tested as a 11-valent vaccine (PCV-11), but serotype 3 was removed from the formulation because it was not found to induce an adequate immune response.9 Other vaccines are under development that include expanded serotypes coverage or use common pneumococcal proteins, but are unlikely to be introduced in the near future.10 PCV-10 and PCV-13 are currently being rolled out making a review of the impact of PCV-7 timely to inform expected outcome as introductions proceed.
CLINICAL TRIALS OF PCV-7
PCVs have been shown to be effective against IPD in clinical trials across a spectrum of populations. PCV-7 has been the most extensively studied and has demonstrated efficacy against IPD in the general US population: 97% (95% confidence interval [CI]: 83, 99.9) efficacy against IPD caused by vaccine serotypes (VT) and 89% efficacy against all IPD regardless of serotype.11 In American Indian populations, the efficacy of PCV-7 against vaccine-type IPD was 77% (95% CI: –9, 95).12 PCV-7 has not been tested in low and middle income countries, but clinical trials of PCV-9 may offer some insight into PCV efficacy in these settings. In South Africa, PCV-9 demonstrated efficacy against pneumococcal disease in both HIV-positive and HIV-negative children. The vaccine was found to prevent 85% (95% CI: 32, 98) of first episodes of VT-IPD in HIV-negative children, and 65% (95% CI: 24, 86) in HIV-positive children.13 In The Gambia, PCV-9 was effective in preventing 77% (95% CI: 51, 90) of VT-IPD.14 The overall performance of PCVs against IPD has been strong, as was demonstrated in a recent meta-analysis by Lucero et al, where the pooled efficacy against VT-IPD was calculated to be 80% (95% CI: 58, 90) across studies globally.15
Multiple clinical trials have measured the efficacy of pneumococcal vaccination on pneumonia. PCV-7 trials in California showed a 30% (95% CI: 11, 46) reduction in radiologically confirmed pneumonia cases,16 and a 4% (nonsignificant) reduction in clinically diagnosed pneumonia.17 A clinical trial evaluating PCV-9 in South Africa found a 25% efficacy (95% CI: 4, 41) against first episodes of radiologically confirmed alveolar consolidation among HIV-negative children.13 An evaluation of PCV-9 in The Gambia found a 37% efficacy (95% CI: 27, 45) against first episode of radiologically confirmed pneumonia, and 7% (95% CI: 1, 12) against clinically diagnosed pneumonia.14 In addition, a 31% (95% CI: 15, 43) reduction in pneumonia with any virus isolate was noted, suggesting a strong association with pneumococcal pneumonia and viral infections.18
Efficacy trials suggested PCV-7 would have a minimal impact on AOM. A Finnish trial demonstrated a 57% (95% CI: 44, 67) efficacy against VT-AOM. However, there was a 33% increase (95% CI: −1, 80) in nonvaccine type (NVT) disease, resulting in an overall 34% reduction (95% CI: 21, 45) in all serotype pneumococcal AOM, and a 6% (nonstatistically significant) reduction in all-cause AOM.19 Other studies of PCV-7 have mirrored these results; pneumococcal-specific AOM was reduced, but there was a limited impact on all-cause AOM (range: –1 to 9% reduction).19–22
Multiple studies have examined the effects of PCV-7 immunization on NP carriage of pneumococcal strains. It is difficult to compare the studies directly, as the study populations varied greatly by age, location, vaccine formulation and other population characteristics. Nevertheless, an overall trend can be elucidated. Overall, vaccination showed little or no effect on carriage rates for combined VT and NVT pneumococcal serotypes.23–26 The efficacy of PCV-7 against VT carriage ranged from 23% to 60%, but was offset by a 44–67% increase in NVT.23–28 In essence, it appears that the NP ecologic niche, cleared of VT pneumococci by immunization is proportionally filled by NVT pneumococci.
Two clinical trials in Africa assessed the effect of a PCV on child mortality.14 In a Gambian trial, more than 17,000 children were randomized to receive either PCV-9 or a placebo along with standard Expanded Program on Immunization vaccinations. The study demonstrated a decrease in all-cause mortality from 30.1 deaths per 1000 child-years in placebo recipients to 25.2 per 1000 child-years in PCV-9 immunized children, translating to an all-cause mortality reduction of 16% (95% CI: 3, 28). A study of PCV-9 in South Africa also showed a reduction in all-cause child mortality, but was not sufficiently powered to draw any statistical conclusions.13
IMPACT OF PCV-7 INTRODUCTION ON PNEUMOCOCCAL DISEASE
Since 2000, the use of PCVs has increased globally (Fig. 1).29 Wealthy countries have taken up the vaccine most readily; 70% of high income countries are currently using PCVs in their national immunization programs. No middle or low income countries used PCV universally in the national immunization program before 2008. However, in the last 3 years, 33 middle and low income countries have introduced PCV, including 9 Global Alliance for Vaccines and Immunization-eligible countries, nations with a gross national income of less than $1,000 per person, whereas another 11 countries have received approval for Global Alliance for Vaccines and Immunization support to introduce PCV.29 Although introduction of PCV-10 and PCV-13 are too recent to show impact, a large amount of long-term data are available describing the impact of PCV-7 from numerous countries in the Americas, Australia and Europe that demonstrate the impact of PCV-7 on IPD, pneumonia and AOM.
The introduction of PCV-7 has resulted in a dramatic reduction in rates of IPD. The impact on VT-IPD has been very consistent across countries, with reductions in incidence ranging from 79% to 100% (Fig. 2),30–38 mirroring the efficacy that was seen in clinical trials. Early studies in the United States, England and Belgium demonstrated a relatively lower impact on VT-IPD compared with other studies, ≤86%, likely because these studies included data within the first few years of introduction, before the full impact of PCV-7 could be felt.30,32,38 Latter studies in the United Kingdom and the United States indicated that 2–3 years of universal vaccination were necessary before disease rates stabilized, after which a ≥98% decrease in VT-IPD rates was seen compared with baseline rates.33,34 In the United States, these reductions have proven sustainable; VT-IPD dropped from 82.7 to 2.2 hospitalizations per 100,000 children less than 5 years of age, and rates have remained stable at these levels for 7 years.34
The overall reduction in incidence of IPD has varied more across studies and nations, from 37% to 80% (Fig. 3).30–40 This variability is largely due to regional differences in the prevailing serotypes before PCV-7 introduction. PCV-7 impact was greatest in Australia, Canada and the United States, where the vaccine serotypes accounted for approximately 80% of IPD before introduction.34,36,37 Impact on hospitalization for IPD also varied globally, with reductions ranging from 9 to 126 hospitalizations per 100,000 children (Table 1). These reductions have proven to be sustainable. Within 3 years of introduction in the United States, all-cause IPD dropped from 98.7 cases per 100,000 children less than 5 years of age to just above 20 cases per 100,000 children in 2002, and has remained low since.34
Before introduction, it was unclear what the impact on NVT-IPD would be. Although some studies saw increases in NVT-IPD and others saw decreases in specific vaccine-related serotypes, a meta-analysis of trials showed no overall efficacy against either.15 Since the introduction of PCV-7, a majority of countries have observed a modest increase in rates of NVT-IPD, with incidences increasing by a factor of 1.4–2.1 compared with the pre-PCV NVT-IPD rates.30,31,33,34,36 A few countries have experienced no significant change in rates of NVT-IPD.32,35,39 A recent systematic analysis presented to the Strategic Advisory Group of Experts on Immunization found that the introduction of PCV-7 resulted in an overall reduction in IPD in children regardless of replacement disease, although the magnitude varied based on location, especially in children older than 5 years of age.41
The serotypes that caused replacement disease have varied. In Belgium, the increase in NVT-IPD incidence resulted from a combination of serotypes 1 and 7F as well as 19A, which increased by 8.3, 6.7 and 7.0 cases per 100,000 children younger than 5 years of age, respectively.31 Similar increases were also seen in the United Kingdom.33 In many countries, serotype 19A has been the cause of the largest increase. In the United States, the incidence of 19A increased from 2.6 to 11.1 cases per 100,000 children younger than 5 years of age, accounting for greater than 70% of the increase in NVT-IPD seen.34 A similar pattern was seen in Australia.36 Serotype 19A is now the most common serotype in Australia, Belgium and the United States.31,34,36 Serotype 6A has decreased after the introduction of PCV-7, which is thought to be due to cross-protection caused by 6B vaccine antigens.42 This decrease in serotype 6A was reported across most studies (range: 45–82% reduction).30,31,33,34,36 A newly recognized serotype, 6C, was until recently identified and reported as serotype 6A. Several retrospective analyses have differentiated 6A and 6C in archived pediatric pneumococcal specimens before and after PCV-7 introduction. These have demonstrated that 6C remains uncommon in pediatric populations, but may have increased after PCV-7 introduction.43,44 However, due to the limited number of isolates available before PCV-7 introduction, strong conclusions on the trend in pediatric 6C disease cannot be drawn at this time.
It is not known to what extent the shifts in NVT-IPD observed after PCV-7 introduction are due to the vaccine. Many countries do not have routine surveillance for pneumococcal disease before the introduction of the vaccine, making it difficult to differentiate secular trends or the effects of antibiotic selection pressure from true replacement disease. The incidence of any one serotype is known to shift over time independent of vaccination.45 In South Korea and Israel, the rate of IPD caused by serotype 19A increased before widespread use of PCV-7, possibly due to the spread of an antibiotic-resistant strain.46 Regardless, in all settings, the overall reduction in VT-IPD disease has outweighed the changes in NVT-IPD, as was noted by the World Health Orgainization’s most recent recomendations.41 Ongoing surveillance is needed to monitor trends in serotype-specific IPD to continue to evaluate the impact of vaccination on serotype-specific disease, and to monitor the impact of the newly introduced expanded serotype PCVs.
PCV-7 has had a dramatic effect on hospitalization due to pneumonia, which, in most studies, is defined as radiologically confirmed pneumonia and includes both community-acquired and hospital-acquired pneumonia, and bacteremic and nonbacteremic pneumonia with indicative radiologic findings. The reductions in the proportion of all-cause pneumonia hospitalization in children has ranged from 13% to 65% after introduction of PCV-7 (Fig. 4).40,47–54 Likewise, impact on the incidence of hospitalization due to all-cause pneumonia has been observed in the Italy, Poland and the United States (Table 2).40,48,49,51,52,54 The wide range of impacts seen may be due to local differences in the common serotypes causing pneumonia, the etiology of pneumonia and duration of time since PCV-7 introduction. This variability is highlighted in the United States, where multiple studies have looked at the reduction in incidence of pneumonia using different populations. The prevaccine incidence of pneumonia in these studies were similar, ranging from 1027 to 1297 pneumonia hospitalizations per 100,000 children younger than 2 years of age, but the reduction varied from 273 to 600, or from 28% to 52% of all-cause pneumonia.40,49,54 Overall, the reductions have resulted in an impressive decrease in hospitalization; it is estimated that the number of hospitalizations in the United States due to all-cause pneumonia in children younger than 2 years of age was reduced by 41,000 in 2004 alone due to PCV-7, whereas over 105,000 hospitalizations would have occurred without the vaccine.49
Relatively little of the observed impact on pneumonia hospitalization has been due to microbiologically confirmed pneumococcal disease, indicating that blood culture has a low sensitivity for detection of pneumococcal pneumonia. In Uruguay, less than 6% of the observed reduction in hospital discharges in children younger than 15 years of age were due to pneumonia with pneumococci isolated,53 whereas only 5% and 14% of the decline in incidence of pneumonia hospitalization in the United States and Italy, respectively, was due to reductions in the number of pneumonia patients with S. pneumoniae isolated.48,54 This mirrors what was seen in randomized control trials and suggests that the majority of pneumococcal pneumonia cases are nonbacteremic and not detected outside of vaccine impact trials.55 More sensitive, noninvasive methods are needed to elucidate the etiology of pneumonia beyond vaccine impact studies.
Few studies have evaluated the impact of PCV on pneumonia outpatient visits, and the findings are less clear than what has been seen for pneumonia hospitalizations. Three studies in the United States have looked at the impact on ambulatory pneumonia, with variable results. One study, which used the MarketScan Databases, found a 41% decrease (P > 0.001) in ambulatory visits, from 99.3 per 1000 children less than 2 years of age before vaccine introduction to 58.5 per 1000 children afterward.54 However, a study that analyzed the National Ambulatory and National Hospital Ambulatory Medical Care Surveys reported a 21% (95% CI: 0.38, 1.24) reduction in risk for all-cause outpatient pneumonia visits in children less than 2 years of age, but the results were not statistically significant.56 A later study that also analyzed the National Ambulatory and National Hospital Ambulatory Medical Care Surveys found no reduction in ambulatory visits after vaccine introduction, and reported wide variations in rates of annual outpatient visits (range: 32.3–49.6 visits per 1000 in children less than 5 years of age).57 Additional prospective studies, particularly from high-burden settings, may further elucidate the role of PCV in reducing pneumonia outpatient visits.
One of the more surprising results of PCV-7 has been its impact on AOM. Reduction in AOM has been consistently reported from a variety of settings, including hospital ambulatory, and emergency room settings, with proportional impacts ranging from 13% to 43% (Fig. 5).48,56,58–60 Two US studies have shown large reductions in the incidence of ambulatory visits in the United States. An analysis of the National Ambulatory and National Hospital Ambulatory Medical Care Surveys database found a decrease from 1415 to 1072 per 1000 children younger than 24 months of age,56 whereas an analysis of the MarketScan Database reported a reduction of 42%, from 2173 to 1244 per 1000 child-years.60 In Italy, a decrease in AOM hospitalizations was noted after PCV-7 introduction; the incidence dropped 58%, from 452 to 188 hospitalizations per 100,000 children under 2 years of age.48 The dramatic reduction in rates of AOM was not anticipated based on the results from PCV randomized control trials that found little impact on all-cause AOM, but could be the result of reduced disease transmission due to herd effects of vaccination.
The impact on AOM has resulted in substantial healthcare savings, exceeding initial assumptions based on impact of IPD and pneumonia alone. In the United States alone, PCV-7 is estimated to save $460 million a year in direct medical expenditure due to ambulatory AOM visits, a 32.3% reduction comparing 2004 with the pre-PCV era.60 An additional benefit of reduction of AOM has been a decrease in the number of antibiotic prescriptions, which decreased 42% after PCV-7 introduction, from 1244 to 722 prescriptions per 1000 person-years.34
The impact of PCV on NP carriage of S. pneumoniae has been highly variable. PCV-7 has demonstrated impact on VT-NP carriage; after PCV-7 introduction, the proportion of pneumococcal NP carriage that is due to VTs has been reduced by 48–92%.61–64 However, serotype replacement is common. In Norway, a 48% reduction in VT-NP carriage was offset completely by NVT-NP carriage, and no overall impact on pneumococci carriage was observed.64 In France, a small but significant reduction in carriage was found, 54% in 1999 to 45% in 2008 (P = 0.01), despite the near elimination of VT-NP carriage, which was reduced from 77% of carriage isolates in 1999 to 4% in 2008.62 Before PCV-7 introduction in France, 77% of NP colonization was due to VT pneumococci. After PCV-7 introduction, only 4% of carriage was caused by VT, but the expansion of NVT colonization resulted in only a small reduction, from 54% in 1999 to 45% in 2008 (P = 0.01).62 By contrast, the Netherlands reported a large reduction in overall pneumococci NP carriage, 57% (odds ratio 0.31–0.59).63 Additional studies are needed to determine the long-term impact of PCV on pneumococcal NP carriage as a marker of disease transmission and the importance of carriage with NVT pneumococci.
Herd immunity, which is thought to be mediated by reduction in transmission of pneumococci to susceptible individuals, is emerging as a large benefit of universal PCV-7 immunization programs. Studies in the United States and the United Kingdom have demonstrated significant reductions in the incidence of IPD in populations not directly vaccinated. The reduction in all serotype IPD ranged from 19% to 62% in age groups 18 years and older,33,34,40 and was clearly the result of reduction in VT-IPD, which decreased by 81–92% in these age groups.33,34As with pediatric IPD, significant replacement disease occurred in older populations. In persons >65 years of age, the incidence of NVT-IPD increased by 32% and 48% in the United States and the United Kingdom, respectively,33,34 but the increase in NVT-IPD diseases was more than compensated by the decrease in VT-IPD. Unlike younger populations, there was no reduction in serotype 6A disease; the number of cases of 6A found has remained stable in 5- to 65-year-olds and increased in those >65 years of age.33,34 However, recent studies in the United States have differentiated archived pneumococcal 6A isolates into serotypes 6A and 6C. Upon differentiation, it appears that the incidence of 6A has been reduced in adult populations after PCV-7 introduction, whereas the incidence of 6C has increased.43,44 Overall, the impact on IPD has been large. In the United States, it is estimated that PCV-7 prevented more cases of VT-IPD in unvaccinated individuals, 2500–29,000 cases per year, than in vaccinated children, where 2700–14,000 cases per year are prevented.34 In total, it is estimated that PCV prevented a total of 211,000 cases and 13,000 deaths from IPD across the United States between 2000 and 2007.
In addition, there have been indications that PCV-7 provides herd immunity against pneumonia. In the United States, a study comparing the 3 years before and after PCV-7 introduction found a 15–26% decrease in the incidence of all-cause pneumonia in nonpediatric age groups.49 However, statistically significant reductions were only observed in 18- to 39-year-olds, where a 26% (95% CI: 4, 43) decrease was reported. A later study examining the rates of all-cause pneumonia hospitalization found that the introduction of PCV-7 was associated with statistically significant decreases in all nonpediatric age groups. Across all age groups this resulted in 788,838 (95% CI: 695, 406–875, 476) fewer hospitalizations due to pneumonia between 2000 and 2006, 90% of which were attributed to indirect disease reduction in adults.40
Impact in High Disease Burden Settings
Low and middle income countries have introduced PCV-7 only recently; therefore, vaccine effectiveness data are limited from these countries. The only available data describes impact on pneumonia, and comes from Poland and Uruguay, which are relatively upper-middle income countries. Disease reduction has been greatest in Poland, with a 65% reduction in pneumonia hospitalizations post–PCV-7 introduction to 2700 cases per 100,000, highlighting the importance of PCVs in high pneumonia incidence countries.52 Similarly, Uruguay observed a 56% reduction in radiologically confirmed pneumonia hospitalizations within 2 years of PCV-7 introduction.53 Although data from these countries have thus far been very promising, additional evidence from lower income countries will improve our understanding of the effectiveness of PCV in high pneumonia burden countries.
The impact of PCV-7 on IPD has not yet been demonstrated in middle and low income countries. However, high disease burden populations within high income countries have been studied extensively, and may offer an insight into the impact that will be observed in low and middle income countries. Before PCV-7, the incidence of IPD in White Mountain Apache, Alaskan Natives and Indigenous Australian children younger than 2 years of age were 934, 403 and 120 per 100,000 children, respectively, much higher than the general populations of the United States and Austraila.36,65,66 However, the PCV-7 was highly effective in these populations; VT-IPD decreased by over 92% in each setting. The impact on NVT and all serotype IPD has been more varied. In Alaskan Natives, an initial reduction in IPD of 67% was noted between 2001 and 2003 compared with the pre–PCV-7 introduction period, 1995 to 2000, which was the result of the near elimination of VT-IPD. However a large increase in NVT-IPD, predominantly serotypes 19A and 7F, occurred in the following years, blunting the impact of the vaccine on all-cause IPD; the incidence of IPD was reduced by 39% when comparing 1995–2000 with 2004–2006.65 In contrast, IPD rates in White Mountain Apache children less than 2 years of age fell by 70%, to 282 in children younger than 2 years of age, with no evidence of replacement disease as of 2006.66 The effectiveness of PCV-7 was limited in Indigenous Australian children with a 36% reduction in IPD incidence (all serotypes) despite 93% reduction in VT-IPD. This was due to the relatively low serotype coverage in this population: VT-IPD accounted for less than half of disease before introduction.36 These observations suggest that introducing PCV in high-burden settings will have varied impact on all-cause pneumococcal disease based on the serotype coverage of the vaccine among the respective populations.
THE IMPLEMENTATION OF PCV-10 AND PCV-13
As global supply increases, PCV-10 and PCV-13 are being rolled out and are replacing PCV-7 in national programs. In addition, the uptake in low and middle income countries has been accelerated by advanced market commitments championed by the Global Alliance for Vaccines and Immunization Alliance, which secures a market for PCV if the vaccine is sold at a set price of $3.50 and meets a prespecified serotype coverage.67 Although the efficacy of PCV-10 and PCV-13 have not been tested as extensively as PCV-7, it is thought that they will be as efficacious against VT disease due to demonstrated noninferiority of serologic studies when compared with PCV-7.42 Components of PCV-13 (including PCV-7) have shown impact against IPD and pneumonia and long-term immunogenicity.13,14,68 The efficacy of PCV-10 against pneumonia has recently been documented,69 and the 11-valent formulation demonstrated high efficacy in clinical trials against all-cause AOM due to reduction of both pneumococcal and H. influenzae AOM.9
The need for PCV-10 and PCV-13 is most apparent in Africa and Asia, where approximately 50% of invasive serotypes are not covered by the PCV-7, but PCV-10 and PCV-13 cover >70% of serotypes (Table 3). As these vaccines role out in lower income countries, it will be important to monitor the vaccine impact and continued effectiveness of PCV to sustain support for continued and new use of PCV in national immunization programs. Furthermore, the need for PCV-10 and PCV-13 is becoming apparent in countries that are currently using PCV-7 as VT-IPD disappears, resulting in proportional increases in NVT-IPD in settings with replacement disease and increased rates of antibiotic-resistant strains of disease. In countries where serotype 19A has seen a large increase, protection against 19A will be critical to determine which vaccine is appropriate to use. It is expected that PCV-13 will provide protection against 19A based on immunogenicity studies, whereas it is unknown if the presence of serotype 19F in PCV-10 will provide cross-protection against 19A. Based solely on the serotypes present in each vaccine, PCV-10 covers 12% of invasive isolates in the United States post–PCV-7 introduction, whereas PCV-13 covers 68% of serotypes, largely due to the presence of 19A.34 In other respects, PCV-10 may hold some advantages over PCV-13 due to prevention of AOM caused by both S. pneumoniae and nontypeable H.influenzae.9 However, without head-to-head trials it is difficult to determine whether either vaccine has a clear advantage over the other. Continued monitoring of PCV-10 and PCV-13 vaccine impact after introduction will be important to determine the relative impact of both of these vaccines. However, both vaccines have potential to make a significant impact beyond what has been observed with PCV-7.
Clinical trials have proven PCVs to be effective against IPD and all-cause pneumonia in a variety of populations around the world, as well as in preventing all-cause child mortality in The Gambia. The impact of routine pediatric vaccination with PCV-7 in Europe, the Americas and Australia has been significant for IPD, pneumonia and AOM, and there is evidence of additional disease burden reduction in nonvaccinated children and adults in the United Kingdom and the United States through herd immunity. A modest increase in nonvaccine serotype disease has been observed in most countries where PCV-7 has been introduced, but the overall impact on pneumococcal disease has been substantial in all countries. Although clinical trial data on PCV efficacy is available for high disease burden settings, vaccine effectiveness data remain limited due to only the recent introduction of PCV. PCV vaccine impact data from low burden settings and high-burden populations within these countries suggest an important disease reduction potential for PCV in these settings. Vaccine impact data from lower income countries are forthcoming, as are data on the newly introduced PCV-10 and PCV-13 vaccines. This information will be instrumental in determining the appropriate use of these vaccines and in sustaining further introduction of pneumococcal conjugate vaccines.
1. O’Brien KL, Wolfson LJ, Watt JP, et al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet. 2009;374:893–902
2. Johnson HL, Deloria-Knoll M, Levine OS, et al. Systematic evaluation of serotypes causing invasive pneumococcal disease among children under five: the pneumococcal global serotype project. PLoS Med. 2010;7:e1000348
3. Lynch JP 3rd, Zhanel GG. Streptococcus pneumoniae: epidemiology, risk factors, and strategies for prevention. Semin Respir Crit Care Med. 2009;30:189–209
4. Hendley JO, Sande MA, Stewart PM, et al. ICarriage rates and distribution of types. J Infect Dis. 1975;132:55–61
5. American Academy of Pediatric Subcommittee on Management of Acute Otitis Media.. Diagnosis and management of acute otitis media. Pediatrics. 2004;113:1451–1465
6. McIntosh ED. Treatment and prevention strategies to combat pediatric pneumococcal meningitis. Expert Rev Anti Infect Ther. 2005;3:739–750
7. Atkinson W, Hamborsky J, McIntyre L, et al.Centers for Disease Control and Prevention.Epidemiology and Prevention of Vaccine-Preventable Diseases.. 200810th ed. Washington, DC Public Health Foundation
8. Eskola J. Immunogenicity of pneumococcal conjugate vaccines. Pediatr Infect Dis J. 2000;19:388–393
9. Schuerman L, Borys D, Hoet B, et al. Prevention of otitis media: now a reality? Vaccine. 2009;27:5748–5754
10. Rodgers GL, Klugman KP. The future of pneumococcal disease prevention. Vaccine. 2011;29(suppl 3):C43–C48
11. Black S, Shinefield H. Safety and efficacy of the seven-valent pneumococcal conjugate vaccine: evidence from Northern California. Eur J Pediatr. 2002;161(suppl 2):S127–S131
12. O’Brien KL, Moulton LH, Reid R, et al. Efficacy and safety of seven-valent conjugate pneumococcal vaccine in American Indian children: group randomised trial. Lancet. 2003;362:355–361
13. Klugman KP, Madhi SA, Huebner RE, et al. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med. 2003;349:1341–1348
14. Cutts FT, Zaman SM, Enwere G, et al. Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial. Lancet. 2005;365:1139–1146
15. Lucero MG, Dulalia VE, Nillos LT, et al. Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and X-ray defined pneumonia in children less than two years of age. Cochrane Database Syst Rev. 2009;4 CD004977
16. Hansen J, Black S, Shinefield H, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than 5 years of age for prevention of pneumonia: updated analysis using World Health Organization standardized interpretation of chest radiographs. Pediatr Infect Dis J. 2006;25:779–781
17. Black SB, Shinefield HR, Ling S, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J. 2002;21:810–815
18. Madhi SA, Klugman KP. Vaccine Trialist GroupA role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med. 2004;10:811–813
19. Eskola J, Kilpi T, Palmu A, et al. Finnish Otitis Media Study GroupEfficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403–409
20. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in childrenNorthern California Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J. 2000;19:187–195
21. Fireman B, Black SB, Shinefield HR, et al. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J. 2003;22:10–16
22. Kilpi T, Ahman H, Jokinen J, et al. Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Clin Infect Dis. 2003;37:1155–1164
23. Cheung YB, Zaman SM, Nsekpong ED, et al. Nasopharyngeal carriage of Streptococcus pneumoniae in Gambian children who participated in a 9-valent pneumococcal conjugate vaccine trial and in their younger siblings. Pediatr Infect Dis J. 2009;28:990–995
24. Dagan R, Givon-Lavi N, Zamir O, et al. Reduction of nasopharyngeal carriage of Streptococcus pneumoniae after administration of a 9-valent pneumococcal conjugate vaccine to toddlers attending day care centers. J Infect Dis. 2002;185:927–936
25. Mbelle N, Huebner RE, Wasas AD, et al. Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine. J Infect Dis. 1999;180:1171–1176
26. Obaro SK, Adegbola RA, Chang I, et al. Safety and immunogenicity of a nonavalent pneumococcal vaccine conjugated to CRM197 administered simultaneously but in a separate syringe with diphtheria, tetanus and pertussis vaccines in Gambian infants. Pediatr Infect Dis J. 2000;19:463–469
27. O’Brien KL, Millar EV, Zell ER, et al. Effect of pneumococcal conjugate vaccine on nasopharyngeal colonization among immunized and unimmunized children in a community-randomized trial. J Infect Dis. 2007;196:1211–1220
28. Dagan R, Muallem M, Melamed R, et al. Reduction of pneumococcal nasopharyngeal carriage in early infancy after immunization with tetravalent pneumococcal vaccines conjugated to either tetanus toxoid or diphtheria toxoid. Pediatr Infect Dis J. 1997;16:1060–1064
29. International Vaccine Access Center.Vaccine Information Management System.. Baltimore, MD International Vaccine Access Center at Johns Hopkins Bloomberg School of Public Health. Database accessed June 30, 2011.
30. Foster D, Walker AS, Paul J, et al. Reduction in invasive pneumococcal disease following implementation of the conjugate vaccine in the Oxfordshire region, England. J Med Microbiol. 2011;60(Pt 1):91–97
31. Hanquet G, Lernout T, Vergison A, et al. Impact of conjugate 7-valent vaccination in Belgium: addressing methodological challenges. Vaccine. 2011;29:2856–2864
32. Harboe ZB, Valentiner-Branth P, Benfield TL, et al. Early effectiveness of heptavalent conjugate pneumococcal vaccination on invasive pneumococcal disease after the introduction in the Danish Childhood Immunization Programme. Vaccine. 2010;28:2642–2647
33. Miller E, Andrews NJ, Waight PA, et al. Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study. Lancet Infect Dis. 2011;11:760–768
34. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010;201:32–41
35. Vestrheim DF, Løvoll O, Aaberge IS, et al. Effectiveness of a 2+1 dose schedule pneumococcal conjugate vaccination programme on invasive pneumococcal disease among children in Norway. Vaccine. 2008;26:3277–3281
36. Williams SR, Mernagh PJ, Lee MH, et al. Changing epidemiology of invasive pneumococcal disease in Australian children after introduction of a 7-valent pneumococcal conjugate vaccine. Med J Aust. 2011;194:116–120
37. Kellner JD, Vanderkooi OG, MacDonald J, et al. Changing epidemiology of invasive pneumococcal disease in Canada, 1998-2007: update from the Calgary-area Streptococcus pneumoniae research (CASPER) study. Clin Infect Dis. 2009;49:205–212
38. Hennessy TW, Singleton RJ, Bulkow LR, et al. Impact of heptavalent pneumococcal conjugate vaccine on invasive disease, antimicrobial resistance and colonization in Alaska Natives: progress towards elimination of a health disparity. Vaccine. 2005;23:5464–5473
39. Rückinger S, van der Linden M, Reinert RR, et al. Reduction in the incidence of invasive pneumococcal disease after general vaccination with 7-valent pneumococcal conjugate vaccine in Germany. Vaccine. 2009;27:4136–4141
40. Simonsen L, Taylor RJ, Young-Xu Y, et al. Impact of pneumococcal conjugate vaccination of infants on pneumonia and influenza hospitalization and mortality in all age groups in the United States. MBio. 2011;2:e00309–e00310
41. Strategic Advisory Group of Experts on Immunization.. Meeting of the Strategic Advisory Group of Experts on Immunization, November 2011— conclusions and recommendations. Wkly Epidemiol Rec. 2012;87:1–16
42. Zangeneh TT, Baracco G, Al-Tawfiq JA. Impact of conjugate pneumococcal vaccines on the changing epidemiology of pneumococcal infections. Expert Rev Vaccines. 2011;10:345–353
43. Carvalho Mda G, Pimenta FC, Gertz RE Jr, et al. PCR-based quantitation and clonal diversity of the current prevalent invasive serogroup 6 pneumococcal serotype, 6C, in the United States in 1999 and 2006 to 2007. J Clin Microbiol. 2009;47:554–559
44. Park IH, Moore MR, Treanor JJ, et al. Differential effects of pneumococcal vaccines against serotypes 6A and 6C. J Infect Dis. 2008;198:1818–1822
45. Black S. The volatile nature of pneumococcal serotype epidemiology: potential for misinterpretation. Pediatr Infect Dis J. 2010;29:301–303
46. Reinert R, Jacobs MR, Kaplan SL. Pneumococcal disease caused by serotype 19A: review of the literature and implications for future vaccine development. Vaccine. 2010;28:4249–4259
47. De Wals P, Robin E, Fortin E, et al. Pneumonia after implementation of the pneumococcal conjugate vaccine program in the province of Quebec, Canada. Pediatr Infect Dis J. 2008;27:963–968
48. Durando P, Crovari P, Ansaldi F, et al. Universal childhood immunisation against Streptococcus pneumoniae: the five-year experience of Liguria Region, Italy. Vaccine. 2009;27:3459–3462
49. Grijalva CG, Nuorti JP, Arbogast PG, et al. Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis. Lancet. 2007;369:1179–1186
50. Jardine A, Menzies RI, McIntyre PB. Reduction in hospitalizations for pneumonia associated with the introduction of a pneumococcal conjugate vaccination schedule without a booster dose in Australia. Pediatr Infect Dis J. 2010;29:607–612
51. Lee GE, Lorch SA, Sheffler-Collins S, et al. National hospitalization trends for pediatric pneumonia and associated complications. Pediatrics. 2010;126:204–213
52. Patrzalek M, Albrecht P, Sobczynski M. Significant decline in pneumonia admission rate after the introduction of routine 2+1 dose schedule heptavalent pneumococcal conjugate vaccine (PCV7) in children under 5 years of age in Kielce, Poland. Eur J Clin Microbiol Infect Dis. 2010;29:787–792
53. Pírez MC, Algorta G, Cedrés A, et al. Impact of universal pneumococcal vaccination on hospitalizations for pneumonia and meningitis in children in Montevideo, Uruguay. Pediatr Infect Dis J. 2011;30:669–674
54. Zhou F, Kyaw MH, Shefer A, et al. Health care utilization for pneumonia in young children after routine pneumococcal conjugate vaccine use in the United States. Arch Pediatr Adolesc Med. 2007;161:1162–1168
55. Grijalva CG. Recognising pneumonia burden through prevention. Vaccine. 2009;27(Suppl 3):C6–C8
56. Grijalva CG, Poehling KA, Nuorti JP, et al. National impact of universal childhood immunization with pneumococcal conjugate vaccine on outpatient medical care visits in the United States. Pediatrics. 2006;118:865–873
57. Kronman MP, Hersh AL, Feng R, et al. Ambulatory visit rates and antibiotic prescribing for children with pneumonia, 1994-2007. Pediatrics. 2011;127:411–418
58. Stamboulidis K, Chatzaki D, Poulakou G, et al. The impact of the heptavalent pneumococcal conjugate vaccine on the epidemiology of acute otitis media complicated by otorrhea. Pediatr Infect Dis J. 2011;30:551–555
59. Wals PD, Carbon M, Sévin E, et al. Reduced physician claims for otitis media after implementation of pneumococcal conjugate vaccine program in the province of Quebec, Canada. Pediatr Infect Dis J. 2009;28:e271–e275
60. Zhou F, Shefer A, Kong Y, et al. Trends in acute otitis media-related health care utilization by privately insured young children in the United States, 1997-2004. Pediatrics. 2008;121:253–260
61. Huang SS, Hinrichsen VL, Stevenson AE, et al. Continued impact of pneumococcal conjugate vaccine on carriage in young children. Pediatrics. 2009;124:e1–11
62. Dunais B, Bruno-Bazureault P, Carsenti-Dellamonica H, et al. A decade-long surveillance of nasopharyngeal colonisation with Streptococcus pneumoniae among children attending day-care centres in south-eastern France: 1999-2008. Eur J Clin Microbiol Infect Dis. 2011;30:837–843
63. Spijkerman J, van Gils EJ, Veenhoven RH, et al. Carriage of Streptococcus pneumoniae 3 years after start of vaccination program, the Netherlands. Emerging Infect Dis. 2011;17:584–591
64. Vestrheim DF, Høiby EA, Aaberge IS, et al. Impact of a pneumococcal conjugate vaccination program on carriage among children in Norway. Clin Vaccine Immunol. 2010;17:325–334
65. Singleton RJ, Hennessy TW, Bulkow LR, et al. Invasive pneumococcal disease caused by nonvaccine serotypes among alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA. 2007;297:1784–1792
66. Lacapa R, Bliss SJ, Larzelere-Hinton F, et al. Changing epidemiology of invasive pneumococcal disease among White Mountain Apache persons in the era of the pneumococcal conjugate vaccine. Clin Infect Dis. 2008;47:476–484
67. . A new market to save lives from pneumococcal disease. Lancet Infect Dis. 2011;11:73
68. Madhi SA, Adrian P, Kuwanda L, et al. Long-term immunogenicity and efficacy of a 9-valent conjugate pneumococcal vaccine in human immunodeficient virus infected and non-infected children in the absence of a booster dose of vaccine. Vaccine. 2007;25:2451–2457
69. Tregnaghi M, Sáez-Llorens X, López P, et al. Evaluating the efficacy of 10-valent pneumococcal non-typeable Haemophilus influenzae protein-d conjugate vaccine (PHiD-CV) against community-acquired pneumonia in Latin America.