Pediatric Infectious Disease Journal:
Evolving Role of 13-valent Pneumococcal Conjugate Vaccine in Clinical Practice
Azzari, Chiara MD, PhD*; Martinón-Torres, Federico MD, PhD†; Schmitt, Heinz-Josef MD, PhD‡; Dagan, Ron MD§
From the *Department of Paediatrics, University of Florence, Meyer Children’s University-Hospital, Viale Pieraccini 24, Firenze, Italy; †Pediatric Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain, and Vaccine Research Unit, Healthcare Research Institute of Santiago, Spain; ‡Medical Department Group and Scientific Affairs, Pfizer Vaccines, Paris, France; and §Pediatric Infectious Disease Unit, Soroka University Medical Center, and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Accepted for publication February 25, 2014.
This article is based on a symposium at the 31st Annual Meeting of the European Society for Paediatric Infectious Diseases, Milan Italy, May 28 to June 1, 2013, which was sponsored by Pfizer.
C.A. has received research grants and/or honoraria as a consultant/advisor and/or speaker, and conducted vaccine trials from GlaxoSmithKline, Sanofi Pasteur MSD, Pfizer Inc/Wyeth and Novartis. F.M.T. has received research grants and/or honoraria as a consultant/advisor and/or speaker and conducted vaccine trials from GlaxoSmithKline, Sanofi Pasteur MSD, Pfizer Inc/Wyeth, Novartis, Merck and MedImmune. During the production of this manuscript, F.M.T. received funding from the European Union’s seventh Framework program under EC-GA nº.279185 (EUCLIDS), from Instituto Carlos III (Intensificación de la actividad investigadora) and Fondo de Investigación Sanitaria (FIS; PI070069/PI1000540) del plan nacional deI+D+I and “fondos FEDER”. H.J.S. is an employee of Pfizer. R.D. has received grants/research support from Pfizer, Berna/Crucell and MSD; he has been a scientific consultant for Pfizer, Berna/Crucell, GlaxoSmithKline, Novartis, MSD and a speaker for Pfizer, Berna/Crucell and GlaxoSmithKline.
The authors have no other funding or conflicts of interest to disclose.
Address for correspondence: Ron Dagan, MD, Pediatric Infectious Disease Unit, Soroka University Medical Center, PO Box 151, Beer-Sheva 84101, Israel. E-mail: email@example.com.
Since the introduction of 7-valent pneumococcal conjugate vaccine (PCV7), PCVs with extended coverage have become available, and there is emerging global evidence that these vaccines, in particular PCV13, have further reduced rates of invasive pneumococcal disease compared with PCV7. The present article aims to address emerging topics related to PCV13 use in routine clinical practice; specifically: (1) the potential role of high-valent PCVs in reducing pneumococcal disease burden; (2) the impact of PCVs on nasopharyngeal carriage and how this may contribute to reductions in otitis media and pneumonia, as well as the prevalence of resistant pneumococcal strains; (3) new PCV13 indications and (4) importance of schedule adherence for PCV in the prevention of cases of vaccine serotype-specific invasive pneumococcal disease. The beneficial effects of PCVs in protecting individuals from a wide spectrum of pneumococcal diseases can be increased by improving the vaccine coverage and adhering to the recommended vaccination schedules. There is increasing evidence that PCV13 has reduced much of the post-PCV7 burden of pneumococcal diseases in the pediatric community, including reducing pneumococcal colonization and the incidence of invasive pneumococcal disease and mucosal diseases. This has also led to a reduction in antibiotic-resistant pneumococcal diseases. The role of PCV13 in clinical practice is evolving, with PCV13 now available for children and adolescents between the ages of 6 weeks and 17 years, thus ensuring that children in all age groups can be protected against vaccine-serotype pneumococcal diseases. Continued surveillance is warranted to monitor the impact of PCV13 on disease burden.
Since the introduction of the 7-valent pneumococcal conjugate vaccine (PCV) in 2000, new PCVs with additional serotype coverage have become available. PCV10 comprises serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F and is indicated for immunization against invasive pneumococcal diseases (IPD), pneumonia and acute otitis media (AOM) in infants and children from 6 weeks up to 5 years of age.1 PCV13 has an additional 3 serotypes (3, 6A and 19A) and is licensed for the prevention of IPD, pneumonia and AOM caused by Streptococcus pneumoniae in infants and children from 6 weeks up to the age of 17 years and for the prevention of IPD in individuals aged ≥18 years including the elderly.2 National pneumococcal vaccination recommendations for adults differ among countries, with some such as the United States having risk-based programs, whereas others such as Greece having age-based vaccination programs.3,4
The present article aims to address relevant issues and arising questions related to the use of PCV13 in routine clinical practice, namely: (1) the potential role of high-valent PCVs, in particular PCV13, in reducing the burden of pneumococcal diseases, (2) the impact of PCVs on nasopharyngeal carriage and how this may be linked to reductions in AOM and pneumonia, as well as the prevalence of resistant pneumococcal strains; (3) the new indications of PCV13 and (4) the importance of PCV schedule adherence in the prevention of cases of vaccine serotype-specific IPD.
After the first 7 years of implementation of universal PCV immunization programs in the infant population, reassuring data on the effectiveness of PCV7 on IPD have been gathered. The impact of PCV7 on pneumococcal diseases has been consistent when evaluated by different methods and in different age groups and populations, all over the world.5–8 A review of the literature reported a median rate reduction of 90.1% (range 39.9–99.1%) for vaccine-type IPD (VT-IPD) in vaccine-eligible children (aged <2 or <5 years, depending on the study).6 Consistent reductions in VT-IPD (ranging from 79% to 100%) have also been reported across a number of high-income, low-disease burden countries after the introduction of PCV7.9 Reductions in all-type IPD were also reported within vaccine-eligible children, as well as reductions in VT-IPD and all-type IPD in age groups not eligible for vaccination,6,9 demonstrating a remarkable indirect (herd) protection against pneumococcal diseases within the community (ie, reducing transmission to susceptible individuals not routinely vaccinated).9 PCV7 has also reduced the burden of AOM and pneumonia in children.10,11 Griffin et al12 reported 47,000 fewer annual hospitalizations because of pneumonia in US children <2 years of age between 2007 and 2009, based on rates before PCV7 introduction (during 1997–1999).
Emerging evidence suggests that PCV13 vaccination has reduced much of the remaining burden of vaccine-type pneumococcal diseases globally, particularly with respect to the emerging serotypes 19A and 7F. Reductions in additional PCV13 serotype-specific and all-type incidences of IPD in children have been reported in the United States, Denmark, Germany, Greece, Spain and the United Kingdom.13–19 Furthermore, overall declines in nasopharyngeal carriage of the additional 6 serotypes in PCV13 (1, 3, 5, 6A, 7F and 19A) at least in the first months after vaccination have been observed in children aged <12 months in a US study, as well as reductions in the carriage of serotypes 19A and 6C in children ≤6 years of age in Portugal and carriage of PCV13 serotypes in children <2 years of age with AOM in France.20–22 PCV13 has also been found to result in lower rates of nasopharyngeal colonization than PCV7 for 4 additional PCV13 serotypes (1, 6A, 7F and 19A), and serotypes 6C and 19F in healthy infants within an Israeli randomized trial.23
PNEUMOCOCCAL MUCOSAL TRIO: CARRIAGE, AOM AND PNEUMONIA
Nasopharyngeal carriage is the source of spread of the pneumococcus in the community, a prerequisite for the resulting diseases such as mucosal infections (otitis media and pneumonia), as well as invasive infections.24 A link has been demonstrated between capsular polysaccharide biochemical structure and carriage prevalence.25 Serotypes consisting of capsules with a polysaccharide that is less metabolically costly (ie, with fewer carbons per repeat unit) are more heavily encapsulated, are able to avoid neutrophil-mediated killing and are more likely to colonize the nasopharynx. There are, however, notable exceptions; some serotypes that have low metabolic costs are rarely found in nasopharyngeal carriage (eg, serotype 3), suggesting that other factors may influence the capacity of specific serotypes to colonize the nasopharynx.25
Those serotypes that are more successful in colonizing the nasopharynx are potentially subjected to prolonged or multiple exposures to antibiotic drugs, which can lead to antibiotic resistance. Thus, a vicious cycle may be observed, where prolonged carriage exposes these serotypes to antibiotic resistance, which in turn provides an advantage for the carried antibiotic-resistant serotypes in an antibiotic pressured environment. Pneumococcal serotypes can be divided into 3 groups according to their capacity for colonization. The “prime league” players (ie, those most often carried and found globally) comprise serotypes 6A, 6B, 14, 19A, 19F and 23F.25–29 Serotypes that are important “second league” players, such as serotypes 10A, 11A, 15A, 15B/C, 33F and 35B, have a somewhat lower capacity to colonize but are still more common than others.25,30 Furthermore, when the carriage of “prime league” serotypes is reduced by vaccination, the “second league” serotypes become unmasked with these becoming the dominant colonizing serotypes.25 A third group of serotypes, such as serotypes 1, 4, 5, 7F, 8 and 12F are highly invasive and associated with severe disease, mainly in outbreaks.28,31–33 However, they are not often carried and constitute a “league of their own” (ie, poorly carried but highly invasive).
Virulent serotypes have been identified for IPD, pneumonia and AOM. A number of studies have compared the incidence of serotypes in isolates from children with IPD (≤5 years of age) with the incidence in nasopharyngeal isolates to determine the invasiveness of specific serotypes. Within these studies (conducted in Chile, Finland, Israel, United Kingdom, the Czech Republic and Taiwan), serotypes 4, 6B, 9V, 14, 18C and 19F (included in PCV7/PCV13) and 19A, 1 and 5 (included in PCV13) had significant odds ratios or invasive indices for IPD indicating their disease potential.31–36 Similarly, Shouval et al33 determined the disease potential of specific serotypes for AOM by comparing the serotype prevalence in middle ear fluid obtained from children with AOM <3 years of age (n = 3330) with those isolated from the nasopharynx in healthy children (n = 1763). Serotypes 1, 3, 5, 18C, 19A and 19F were found to be associated with higher disease potential for AOM (Fig. 1). The pneumococcal serotype-specific disease potential for community-acquired alveolar pneumonia (CAAP) in children aged <5 years has also been estimated by comparing nasopharyngeal pneumococcal carriage in patients with pneumonia with carriage in healthy controls (603 and 1504 isolates, respectively).37 As serotype 6B was the most common serotype in the healthy controls, as well as being common in patients with CAAP, the odds ratios for pneumococcal carriage during pneumonia versus healthy controls in various serotypes were compared with the odds ratio for serotype 6B. Serotypes 1, 5, 7F, 9V, 14, 19A, 22F and 33F had significantly higher odds ratios versus that of serotype 6B (Fig. 2). However, as bacteriology was only determined in nasopharyngeal isolates in this study, it is not known whether these serotypes were present in the pleural fluid, empyema or blood cultures. Serotypes 1, 5 and 14 have also been implicated in pediatric pneumonia in children <5 years of age from the Gambia based on the serotyping of paired nasopharyngeal and lung fluid aspirates by a MassTag polymerase chain reaction assay (a multiplex molecular tool that uses distinct low-molecular-mass tags to identify bacteria).38
There is emerging evidence that PCV13 has widened the spectrum of carriage reduction compared with PCV7. Within a randomized trial comparing PCV13 with PCV7 for the prevention nasopharyngeal colonization in healthy infants (aged 7–24 months), a reduced rate of acquisition and carriage of serotypes 1, 6A, 6C, 7F, 19A and 19F was observed.23 Acquisition and carriage of penicillin-, macrolide- and clindamycin-nonsusceptible S. pneumoniae, as well as that of dual penicillin and erythromycin-nonsusceptible and multidrug-resistant strains, was also significantly lower in children vaccinated with PCV13 compared with those vaccinated with PCV7.39 However, in this respect, there have been reports of antibiotic resistance among the “second league” serotypes such as 15A, 15B/C and 35B.30,40–42 Therefore, long-term surveillance is needed before a definitive reduction in resistance is confirmed. Widespread use of PCV7 followed by PCV13 has also led to a sharp reduction in the nasopharyngeal carriage of vaccine serotypes, as observed in sick children <5 years of age attending the pediatric emergency room in Southern Israel. This serotype-specific reduction of carriage after PCV7/PCV13 vaccination has been highly associated with serotype-specific reduced burden of AOM.43 A study in Italian children (aged 6–59 months) analyzed by real-time polymerase chain reaction44 confirmed that multiple colonization by different serotypes is extremely common in children and demonstrated that the rate of vaccine serotypes found in nasopharyngeal carriers is reduced in the first year after PCV7 vaccination. However, thereafter serotype carriage progressively increased, so that PCV7 serotypes were commonly found in vaccinated children in the following year after vaccination.45
Weinberger et al46 assessed the effect of PCV vaccination on the incidence of radiologically confirmed CAAP in children <3 years of age from Southern Israel. They observed a mild decrease in alveolar pneumonia in children <3 years of age after the introduction of PCV7, but once combined PCV7/PCV13 vaccination rates (≥2 doses) reached 85% and PCV7 was largely replaced by PCV13, a marked decrease in alveolar pneumonia was observed. Similarly, a ≥75% decline in vaccine serotype-specific pneumococcal otitis media, necessitating middle ear fluid cultures in Israeli children <2 years of age, has been observed after the introduction of PCV13 with >90% reduction in PCV13 serotype-specific disease.47 A sharp reduction in nonsusceptible S. pneumoniae serotypes was also reported in these children after the introduction of PCV7, with a further sharp decline after the introduction of PCV13.47,48
These findings suggest a clear and striking serotype-specific association with respect to the impact that PCV7 and PCV13 have on carriage (at least within the first year after vaccination), antibiotic resistance, pneumonia and AOM. Those serotypes that are most often carried are also most often exposed to antibiotic drugs, as well as being more capable of exchanging genomic material with other bacteria. They are also more likely to spread to other individuals. Therefore, the reduction in the carriage of serotypes with a high capacity to colonize by PCV vaccination may contribute to a reduction in antibiotic resistance, as well as the spread and burden of pneumococcal diseases, such as pneumonia and AOM, in children.
NEW INDICATIONS: PREVENTION OF PNEUMOCOCCAL DISEASES IN ALL AGE GROUPS
Although children aged <5 years and adults >50 years of age are particularly vulnerable to pneumococcal diseases,49 some individuals in other age groups are also at increased risk. Factors other than age that increase an individual’s risk of pneumococcal diseases include chronic organ diseases, immunocompromising conditions, increased exposure to pneumococci (eg, to children in daycare), as well as specific behaviors such as smoking or alcohol abuse.50–55
A UK analysis of hospitalization records found that children aged 2–15 years were especially vulnerable to IPD if they had a chronic disease (asplenia/splenic dysfunction; chronic respiratory, heart, kidney or liver disease; diabetes; immunosuppression or HIV), having a 12-fold increased risk of IPD compared with those without a chronic disease.56 An epidemiologic study conducted in hospitalized African children also found a 40-fold increase in IPD cases in HIV-infected children aged <12 years compared with that in noninfected children,57 and high incidences of IPD have also been reported in US children with HIV aged <7 years and ≤18 years.58,59 Other studies have reported increased risks of IPD in children with sickle cell disease or cochlear implants (Table 1).60–62 Adults with HIV are also at increased risk of IPD. A US surveillance study reported a 41% reduction in IPD in adults with HIV after the introduction of PCV7 in childhood vaccination programs, from 1165 cases per 100,000 during 1998–1999 to 685 cases per 100,000 in 2007.63 However, the incidence of IPD (2004–2007) in individuals with HIV was still 40 times greater than in those without HIV. The burden of disease in individuals at risk of pneumococcal infections is of a magnitude that resulted in recommendations for the use of PCV13 in children at risk.
It is not feasible to conduct clinical studies to document immunogenicity, reactogenicity and safety in all types of risk populations. For those with normal immune functions who are at risk of pneumococcal diseases, there is no biological plausibility that there is an impaired immune response to vaccination. To this end, similar PCV13 immunogenicity has been demonstrated in some risk groups compared with healthy volunteers, and these data can be used with appropriate caution to predict immunogenicity in other risk groups. Children with sickle cell disease, who had been previously immunized with 23-valent pneumococcal polysaccharide vaccine, responded well to 2 doses of PCV13 administered 6 months apart, with a 1.73-fold to 7.01-fold increase in immunoglobulin G geometric mean concentrations after the first dose, depending on the serotype.64 The immunogenicity of PCV13 has also been compared in preterm versus full-term infants, using the World Health Organization-established threshold (geometric mean titer >0.35 μg/mL). Although immune responses of the preterm infants were found to be lower than that of full-term infants, the majority of preterm infants achieved the World Health Organization threshold after primary vaccination.65 The immunogenicity of PCV13 has also been demonstrated in children ≤18 years of age with HIV and with a history of 23-valent pneumococcal polysaccharide vaccination, irrespective of highly active antiretroviral therapy use.66
The PCV13 indication in Europe has recently been expanded to include children aged 6–17 years and adults aged ≥18 years.2 As PCV13 has been demonstrated to have the same level of immunogenicity in risk groups (such as those with sickle cell disease or HIV infection) as in healthy volunteers, physicians should be vigilant regarding individuals who are at risk of pneumococcal diseases. Pneumococcal vaccines are recommended in most European countries for individuals at risk of pneumococcal diseases, and physicians should refer to local recommendations for definitions of risk groups and specific recommendations for vaccination.67
IMPORTANCE OF VACCINE UPTAKE AND SCHEDULE ADHERENCE
PCV vaccination has been demonstrated to reduce the burden of pneumococcal diseases in children. For example, within the Madrid region of Spain, the HERACLES surveillance study (2007–2011) demonstrated a 34% reduction in IPD hospitalization rate in children aged <15 years, 11 months after the introduction of PCV13 (dose schedule: 2 + 1 schedule).68 Similarly, in Germany, there has been a decrease in pneumococcal serotypes isolated from patients with IPD since the introduction of PCVs (PCV7 in July 2006, PCV10 in April 2009 and PCV13 in December 2009). By 2008–2009, there was 40% decrease in all-type IPD cases in children <2 years of age, followed by a further decrease during 2011–2012.15 However, a market research survey conducted among parents in some areas of Europe described variable vaccination rates. The uptake of ≥1 dose of PCV in children 19 to 30 months of age varied from 76% to 97% in countries where pneumococcal vaccination is both recommended and reimbursed to, for example, 43% in Austria where PCV vaccination is recommended but not reimbursed. This survey also found rates of pneumococcal vaccination to be lower in children than rates of other routine childhood vaccines [eg, diphtheria-tetanus-pertussis component combination (DTaP)].69
Different pneumococcal vaccination schedules are recommended across Europe, which have been devised by national advisory bodies after consideration of the epidemiology and disease burden and the immunogenicity of the vaccine and its compatibility with other vaccines. Most European countries have adopted the 2 + 1 schedule, with the primary series administered within the first 6 months of life and the booster dose administered between 1 and 2 years of age.67 In these countries, administration of a booster dose may be especially important because immune responses to PCV, particularly to serotypes 6B and 23F, may be lower after 2 infant doses compared with 3 infant doses.70 Vaccine uptake and compliance with the pediatric immunization program and a catch-up program are important to maximize herd protection in countries with a 2 + 1 schedule; this could contribute to protection in vaccinated children during the interval between the second infant dose and the toddler dose. Findings from the parental survey suggest that timely and adequate vaccination (ie, timely completion of primary series and booster doses) is a concern in some countries. These data are also supported by those from other studies reporting the proportion of children completing their primary series or booster dose by their second birthday.71–77 In a Swiss study, rates for complete primary immunization (ie, 3 doses) by the age of 12 months for the recommended vaccine, DTaP, were higher than for PCV7 (≥2 doses; 94% versus 73%, respectively).78 Within this study, timely immunization was defined (according to Swiss immunization recommendations) as 3 doses of DTPa before 12 months, with 4th dose before 24 months of age and ≥1 dose of PCV7 between 12 and 24 months of age. There was also a delay in children receiving a booster dose of PCV7, with only 70% of children receiving the booster by the age of 2 years.78 A similar delay in receipt of PCV doses has been shown in Greece.75
Nonadherence to vaccination schedules can lead to avoidable cases of IPD in nonvaccinated or partially vaccinated individuals. In the Madrid region of Spain, IPD cases have been monitored since the introduction of PCV7 in the national immunization program through to the introduction of PCV13 in the HERACLES surveillance study.79 Among the cases of IPD (caused by PCV13 serotypes) in children <2 years of age, most (75%) occurred in unvaccinated children and there was only 1 case (within 2 days of the 3rd PCV13 dose) in children who had received 3 or more PCV13 doses. Similarly, cases of PCV13-serotype IPD in children <2 years of age reported in Germany have mostly occurred in unvaccinated children or in those who had received an incomplete course of PCV.15
A number of barriers to adherence have been identified including low awareness levels of the benefits of PCV vaccination amongst parents and healthcare professionals, as well as missed appointments resulting in delays in the administration of the booster vaccine.69,77,80 Education of parents and healthcare professionals has been identified as a key strategy by which to improve coverage and schedule adherence with PCVs. Such education would include information concerning the risk of IPD and the importance of timely administration of PCVs, as well as providing reassurance regarding the safety and appropriateness of PCV administration concomitantly with other vaccines (where appropriate). Immunization registers, such as Vaccinet in Belgium, may also help to identify children who have missed doses so that these individuals can be recalled for immunization.81
Universal childhood pneumococcal immunization programs have been successful in reducing the burden of IPD, pneumonia and AOM in children <5 years of age, as well as reducing the incidence of pneumococcal diseases in other age groups in which the vaccine has not been recommended.9,12,82 This suggests that universal immunization programs can improve public health by increasing vaccination rates to a level that will provide herd protection against pneumococcal infections (ie, by reducing transmission to susceptible individuals). These beneficial effects can be further increased by improving adherence to the recommended vaccination schedules to ensure that individuals receive adequate protection and to obtain the maximal public health vaccine benefits.
Recommendations for PCV vaccination in children of all ages (6 weeks to 17 years) who are at risk of pneumococcal diseases are being introduced in many countries. Successful implementation of these guidelines through educational initiatives is warranted.
There is emerging evidence that PCV13 is reducing much of the remaining post-PCV7 burden of pneumococcal diseases in children, particularly against serotypes 19A and 7F. Beyond the effect on IPD, there is now increasing evidence that PCV13 has resulted in further reductions in carriage, pneumonia and otitis media caused by the additional serotypes, as well as significantly reducing antibiotic-resistant pneumococcal diseases. The impact of PCV13 on carriage is highly associated with reductions in IPD and mucosal disease, including those caused by antibiotic-resistant strains. As the role of PCV13 evolves in routine clinical practice, continued surveillance is warranted to monitor its effect on pneumococcal diseases.
The content of this article is based on a symposium (sponsored by Pfizer, Paris, France) held at the 31st Annual Meeting of the European Society for Paediatric Infectious Diseases (2013) in Milan, Italy, May 26 to June 1, 2013. The authors take full responsibility for the content of this article and thank Neostar Communications Ltd, Oxford, United Kingdom (funded by Pfizer, Paris, France) for their assistance in preparing the manuscript, including preparing the first draft in close collaboration with the authors and the collation of author comments.
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pneumococcal diseases; invasive pneumococcal diseases; pneumococcal conjugate vaccine; PCV13
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