Experience with pneumococcal polysaccharide conjugate vaccine (conjugated to CRM197 carrier protein) in children and adults*

  • P. Durando
    Correspondence
    Corresponding author: P. Durando, Vaccines and Clinical Trial Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST of Genoa, Via A. Pastore 1 – 16132 Genoa, Italy
    Affiliations
    Vaccines and Clinical Trial Unit, Department of Health Sciences, University of Genoa and IRCCS AOU San Martino-IST of Genoa, Genoa, Italy
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  • S.N. Faust
    Affiliations
    Southampton NIHR Wellcome Trust Clinical Research Facility, Faculty of Medicine Academic Unit of Clinical and Experimental Sciences and Institute for Life Sciences, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
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  • M. Fletcher
    Affiliations
    Medicines Development Group and Scientific Affairs, Specialty Care Business Unit, Vaccines, Pfizer, Paris, France
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  • P. Krizova
    Affiliations
    Centre for Epidemiology and Microbiology, National Institute of Public Health, Prague, Czech Republic
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  • A. Torres
    Affiliations
    Pneumology Department, Clinic Institute of Thorax (ICT), Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Ciber de Enfermedades Respiratorias CB06/06/0028 (CIBERES), University of Barcelona (UB), Barcelona, Spain
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  • T. Welte
    Affiliations
    Department of Respiratory Medicine, Medizinische Hochschule Hannover, Hannover, Germany
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      Abstract

      Streptococcus pneumoniae-related infections are a major cause of morbidity and mortality in people of all ages worldwide. Pneumococcal vaccine development started in 1911 with a whole cell vaccine and more recently multivalent plain polysaccharide and polysaccharide conjugate vaccines have been developed. The recent vaccines rely on capsular polysaccharide antigens to induce serotype-specific immune responses. We summarize here the presentations on pneumococcal polysaccharide conjugate vaccine (conjugated to CRM197 carrier protein) given during the integrated symposium organized and funded by Pfizer International Operations during the 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 31 March to 3 April 2012, London, UK. A dramatic reduction in the incidence of invasive pneumococcal diseases (IPD) due to vaccine serotypes (VST-IPD) has been reported since the introduction of a hepta-valent pneumococcal conjugate vaccine (PCV7). An indirect (herd) effect has been demonstrated to be associated with PCV7 infant vaccination programmes, with many studies reporting reductions in VST-IPD in populations that are not eligible for PCV7 vaccination. Since 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) has been introduced into national immunization programmes and results from early surveillance suggest that this vaccine also has an impact on the serotypes unique to PCV13, as well as continuing to protect against the PCV7 serotypes. Data from a passive surveillance system in Europe in 2009, for instance, showed that the highest incidence of IPD remains in those aged >65 years and in children <5 years. PCV13 has now been licensed for vaccination of adults >50 years based on safety and immunogenicity data; an efficacy trial is being conducted. Regardless of previous pneumococcal vaccination status, if the use of 23-valent polysaccharide is considered appropriate, it is recommended to give PCV13 first. Novel immunization strategies remain the only practical means to reduce significantly the remaining global mortality and morbidity due to S. pneumoniae in adults.

      Keywords

      Introduction

      Streptococcus pneumoniae-related infections are a major cause of morbidity and mortality in people of all ages worldwide [
      • World Health Organization
      Acute Respiratory Infections (Update September 2009).
      ]. The bacteria can cause invasive pneumococcal diseases (IPD), such as bacteraemia and meningitis, non-invasive infections, such as acute otitis media, sinusitis and mastoiditis, and pneumonia, which can be either invasive (bacteraemic pneumonia) or non-invasive (non-bacteraemic pneumonia). Pneumonia acquired outside healthcare or extended care facilities is known as community-acquired pneumonia (CAP) [
      • Krueger P
      • St Amant O
      • Loeb M
      Predictors of pneumococcal vaccination among older adults with pneumonia: findings from the Community Acquired Pneumonia Impact Study.
      ].
      The clinical burden of IPD is bacteraemia, meningitis and bacteraemic pneumonia. Establishing the burden of IPD depends on laboratory-based surveillance. Although CAP is more prevalent than IPD, it is difficult to estimate the clinical burden of CAP attributable to S. pneumoniae. From the clinical and microbiological points of view, there are several reasons why this is so, including: (i) the heterogeneity of the clinical picture associated with CAP; (ii) physicians often do not request laboratory confirmation of their diagnosis; (iii) the sub-optimal sensitivity of the current standard laboratory test, blood culture, the sensitivity of which is further hindered by frequent early antibiotic therapy during the initial stages of illness and the polymicrobial nature of the infection; and finally, (iv) the difficulty in obtaining detailed laboratory data and clinical phenotyping particularly for patients in the community setting (outpatient and home/office visits). These difficulties are reflected, epidemiologically, in the wide variability of incidence and mortality data reported in the literature for adults over the last 20 years.
      The age-specific incidence of IPD and pneumonia is highest in the younger and older segments of the population, with a rise in adults starting from about 50 years of age [
      • Centers for Disease Control and Prevention
      ,
      • European Centre for Disease Prevention and Control
      ]. Before the introduction of pneumococcal conjugate vaccine (PCV) in infant vaccination programmes, IPD incidence was high in young children. For example, it was estimated that in the USA there were 65 000 cases of IPD annually, with >16 000 (25%) occurring in children <5 years old [
      • Pilishvili T
      • Lexau C
      • Farley MM
      • et al.
      Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine.
      ]. In Europe, before PCV introduction, the reported IPD incidence varied in children <2 years from 1.7 per 100 000 in Sweden to 174 per 100 000 in Spain [
      • McIntosh ED
      • Fritzell B
      • Fletcher MA
      Burden of paediatric invasive pneumococcal disease in Europe, 2005.
      ]. These differences in incidence rates might be explained by different surveillance systems and blood culture practices [
      • European Centre for Disease Prevention and Control
      ]. Globally, pneumococcal disease is estimated to be responsible for >800 000 deaths a year in children <5 years old [
      • O'Brien KL
      • Wolfson LJ
      • Watt JP
      • et al.
      Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates.
      ], most of these being attributed to pneumonia. In addition, 90% of pneumococcal deaths among children <5 years old in the ten countries with the highest pneumococcal death rates in this population were due to pneumonia [
      • O'Brien KL
      • Wolfson LJ
      • Watt JP
      • et al.
      Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates.
      ].
      In Europe, the annual incidence of CAP per 1000 adults has been reported to be 10.8 in Finland, 4.1 in the UK and between 3.7 and 10.1 in Germany [
      • Welte T
      • Kohnlein T
      Global and local epidemiology of community-acquired pneumonia: the experience of the CAPNETZ Network.
      ]. Mortality was reported to be about 4% in outpatients and between 10% and 20% in hospitalized patients. The mortality rate is highest among patients admitted to intensive care units, ranging from 11.1% to 48%, and among older patients [
      • Welte T
      • Torres A
      • Nathwani D
      Clinical and economic burden of community-acquired pneumonia among adults in Europe.
      ].
      Populations around the world are rapidly ageing, which is a demographic indicator of improving global health. The World Health Organisation (WHO) has estimated that the world's population of people 60 years of age and older has doubled since 1980 and is forecast to reach 2 billion by 2050 [
      • World Health Organization
      ]. The WHO projected that hospitalization for pneumococcal pneumonia will increase by 96% and that the total costs for pneumococcal pneumonia will double from $2.5 billion to $5.0 billion [
      • Wroe PC
      • Finkelstein JA
      • Ray GT
      • et al.
      Aging population and future burden of pneumococcal pneumonia in the United States.
      ].
      Another model estimated that in the USA, in 91.5 million adults aged ≥50 years, each year there are 29 000 cases of IPD (27 700 cases of bacteraemia and 1800 cases of meningitis), 502 600 cases of non-bacteraemic pneumococcal pneumonia (198 600 cases requiring hospital care and 304 000 cases treated outside the hospital setting) and 25 400 deaths associated with pneumococcal disease (6200 due to invasive disease and 19 200 due to pneumonia) [
      • Weycker D
      • Strutton D
      • Edelsberg J
      • Sato R
      • Jackson LA
      Clinical and economic burden of pneumococcal disease in older US adults.
      ]. This important clinical burden was estimated to cost $ 3.7 billion and $ 1.8 billion in annual direct and indirect costs, with non-bacteraemic pneumococcal pneumonia accounting for most of these (81% of direct costs and 62% of indirect costs). Individuals suffering from chronic disease or immunosuppression have a higher individual risk for IPD than healthy subjects in the same age group; even in the presence of indirect (herd) protection; consequently, they are at greater risk of infection and disease than same-aged healthy subjects.

      Pneumococcal Vaccine Development

      The first immunotherapy for pneumococcal diseases was an anti-pneumococcal serum discovered in 1891 and commercialized in 1895 [
      • Grabenstein JD
      • Klugman KP
      A century of pneumococcal vaccination research in humans.
      ]. The development of a pneumococcal vaccine started as early as 1911 when a whole cell vaccine first became available (Table 1) [
      • Grabenstein JD
      • Klugman KP
      A century of pneumococcal vaccination research in humans.
      ]. In the late 1940s, the capsules of a number of clinically important serotypes were purified and multivalent plain polysaccharide vaccines became available. In the USA, a 14-valent and then a 23-valent polysaccharide vaccine were registered in 1977 and 1983, respectively. The 23-valent plain polysaccharide (PPV23) vaccine is licensed for administration from the age of 2 years. However, plain polysaccharide vaccines are poorly immunogenic in infants. This limitation has been overcome with the development of conjugate vaccine technology, which has since been applied to a number of vaccine-preventable disease targets.
      TABLE 1The development of pneumococcal immunotherapy and vaccines [
      • Grabenstein JD
      • Klugman KP
      A century of pneumococcal vaccination research in humans.
      ]
      Serum therapy1891 (and was commercially available in 1895)
      Whole cell vaccine1911
      Purified capsular vaccineMid 1930s: multivalent purified capsular vacine
      Plain polysaccharide vaccinesLate 1940s: multivalent polysaccharide vaccine
      Early 1950s: first-generation pneumococcal polysaccharide vaccines on the market
      1977: 14-valent (1, 2, 3, 4, 5, 6A, 7F, 8, 9N, 12F, 18C, 19F, 23F, 25F) vaccine registered in the USA
      1980s: 17-valent (1, 2, 3, 4, 6A, 7F, 8, 9N, 11A, 12F, 14, 15F, 17F, 18C, 19F, 23F, 25) registered in Europe
      1983: 23-valent (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 11F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F) vaccine registered in the USA
      Conjugated polysaccharide vaccines2000: hepta-valent vaccine (PCV-7) (4, 6B, 9V, 14, 18C, 19F, 23F) registered in 2000 in the USA and in 2001 in Europe
      2009: 10-valent (1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F) vaccine registered
      2010: 13-valent (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) vaccine registered
      Investigational vaccinesProtein vaccines, containing specific pneumococcal proteins, such as pneumolysin, choline-binding proteins (PspA, PspC and Lyt A) and lipoproteins (PsaA)
      The first pneumococcal conjugate vaccine (hepta-valent pneumococcal conjugate, PCV7, conjugated to the CRM197 carrier protein) was registered for use in children in 2000 in the USA and in 2001 in Europe. Since 2010, higher-order conjugates, a 10-valent PCV (PCV10, conjugated to protein D, diphtheria toxoid and tetanus toxoid carrier proteins) and a 13-valent PCV (PCV13, conjugated to CRM197 carrier protein) have been licensed. In addition to the paediatric indication, PCV13 has now been licensed in Europe for active immunization for the prevention of invasive disease caused by S. pneumoniae in adults aged ≥50 years and in the USA for the prevention of pneumonia and IPD in adults aged ≥50 years old [
      • Centers for Disease Control and Prevention
      Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the advisory committee on immunization practices (ACIP).
      ,]. In adults, the protective antibody threshold is not known, so in all the pivotal clinical trials, a serotype-specific opsonophagocytosis assay (OPA), which measures functional antibody concentrations, was used as a surrogate to assess potential efficacy against invasive pneumococcal disease (IPD) and pneumonia. OPA geometric mean titres measured 1 month after each vaccination were calculated. The pivotal trials for Prevenar 13 were designed to show that functional OPA antibody responses for the 13 serotypes were non-inferior, and for some serotypes were superior, to the 12 serotypes in common with the licensed 23-valent pneumococcal polysaccharide vaccine (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 14, 19F, 23F) 1 month after vaccine administration. The response to serotype 6A, which is unique to Prevenar 13, was assessed by demonstration of a four-fold increase in the specific OPA titre above pre-vaccination levels [
      • European Medicines Agency
      Assessment report-Prevenar 13 pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) - Procedure No.: EMEA/H/C/001104/II/0028.
      ].

      Mechanisms of Action for Polysaccharide and Conjugate Vaccines

      Streptococcus pneumoniae are polysaccharide-encapsulated, lancet-shaped, gram-positive, facultative-anaerobic organisms. Both the plain polysaccharide and the polysaccharide conjugate vaccines rely on the capsular polysaccharide antigen to induce a serotype-specific immune response. However, vaccines containing plain polysaccharide have a different mechanism of action from those containing polysaccharide conjugated to a carrier protein [
      • Pollard AJ
      • Perrett KP
      • Beverley PC
      Maintaining protection against invasive bacteria with protein-polysaccharide conjugate vaccines.
      ]. The plain polysaccharides are T-cell-independent antigens that simulate immediate B-cell responses by cross-linking the B-cell receptors. This results in B-cell differentiation to plasma cells that can then produce antibodies. The process does not lead to an expansion of serotype-specific B cells, or to the creation of serotype-specific memory B cells. In contrast, conjugated vaccines elicit a T-cell-dependent response. The polysaccharide antigens bind to specific naive B cells, but as the carrier protein is also processed within the B-cell, the peptides produced are presented (via MHC class II molecules) to carrier-peptide-specific helper T cells. The helper T cells are themselves primed to the peptides through interaction with antigen-presenting cells that have also processed the carrier protein [
      • Avci FY
      • Li X
      • Tsuji M
      • Kasper DL
      A mechanism for glycoconjugate vaccine activation of the adaptive immune system and its implications for vaccine design.
      ]. This helper T-cell process therefore enhances the immune response provided by the B cells, so that the antibody response is of greater specificity and functionality. Memory B cells are also induced, which enables an anamnestic response to be elicited after a subsequent dose of the vaccine or enables a booster response on exposure to the antigen during natural infection.

      The Impact of Childhood PCV7 Vaccination

      It is over 10 years since PCV7 was introduced into the US national vaccination programme. PCV7 has been licensed in nearly 100 countries, and included in many national vaccination programmes as either a 3 + 1 (three doses under 6 months plus a booster after 1 year of age), a 2 + 1 (two doses under 6 months plus a booster after 1 year of age) or a 3 +0 (three doses before 1 year of age) dose schedule for immunizing children during the first 2 years of life [
      • World Health Organization
      Pneumococcal vaccines WHO position paper 2012.
      ]. A summary of schedules in the 27 European Union countries and the four European Free Trade Area countries is given in Table 2 [
      • Gruber WC
      • Scott DA
      • Emini EA
      Development and clinical evaluation of Prevnar 13, a 13-valent pneumocococcal CRM197 conjugate vaccine.
      ,
      • Euvac
      Pneumococcal vaccination (PCV) overview in European countries.
      ]. Since its introduction into childhood vaccination programmes, PCV7 has dramatically reduced the incidence of VST-IPD (IPD due to vaccine serotypes) [
      • Myint TH
      • Madhava H
      • Balmer P
      • et al.
      The impact of 7-valent pneumococcal conjugate vaccine on invasive pneumococcal disease: a literature review.
      ]. For example, following the introduction of PCV7 in the USA in 2000, a 100% reduction in VST-IPD in children <5 years was established by 2007. The incidence of all-type IPD in children <5 years was reduced by 76%, from 98.7 cases per 100 000, before PCV7 introduction, to 23.6 cases per 100 000 afterwards [
      • Pilishvili T
      • Lexau C
      • Farley MM
      • et al.
      Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine.
      ]. Although both were highly significant, there was a greater reduction in the incidence of outpatient IPD compared with that of hospitalized IPD; 85.4% (from 67.3 cases per 100 000 to 9.8 cases per 100 000) versus 59.9% (from 31.4 cases per 100 000 to 12.6 cases per 100 000) [
      • Pilishvili T
      • Lexau C
      • Farley MM
      • et al.
      Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine.
      ]. In this study the incidence of meningitis was reported to be significantly reduced by 63.8% (from 4.7 cases per 100 000 to 1.7 cases per 100 000). Similar trends were observed in various European countries, with a 97% reduction of VST-IPD in children <5 years of age in Belgium between 2002 and 2009 [
      • PediSurv
      Surveillance of infectious diseases in children in Belgium [Surveillance des maladies infectieuses chez les enfants en Belgique].
      ], a more than 90% VST-IPD reduction in children <2 years in 2010 in Germany [
      • van der Linden M
      • Weiss S
      • Falkenhorst G
      • Siedler A
      • Imohl M
      • von Kries R
      Four years of universal pneumococcal conjugate infant vaccination in Germany: impact on incidence of invasive pneumococcal disease and serotype distribution in children.
      ], and 90% and 95% reductions in VST-IPD in the Netherlands and Norway, respectively [
      • Rodenburg GD
      • de Greeff SC
      • Jansen AG
      • et al.
      Effects of pneumococcal conjugate vaccine 2 years after its introduction, the Netherlands.
      ,
      • Vestrheim DF
      • Hoiby EA
      • Bergsaker MR
      • Ronning K
      • Aaberge IS
      • Caugant DA
      Indirect effect of conjugate pneumococcal vaccination in a 2 + 1 dose schedule.
      ].
      TABLE 2Overview of pneumococcal conjugate vaccine (PCV) programmes in European Union and European Free Trade Area countries in 2013 (based on [
      • Euvac
      Pneumococcal vaccination (PCV) overview in European countries.
      ])
      CountryYear introduced into programme
      a National except Italy, Spain and Sweden, where the introduction was regional and Poland and Slovenia where the vaccine is recommended for high-risk groups.
      Current schedule
      Austria20122+1
      Belgium20072+1
      Bulgaria20103+1
      Cyprus20082+1
      Czech Republic20103+0
      Denmark20072+1
      EstoniaNot in national immunization programme
      Finland20102+1
      France20062+1
      Germany20063+1
      Greece20063+1
      Hungary20082+1
      Iceland20112+1
      Ireland20082+1
      Italy20062+1
      Latvia20102+1
      LithuaniaNot in national immunization programme
      Luxembourg20032+1
      MaltaNot in national immunization programme
      Netherlands20063+1
      Norway20062+1
      Poland20103+1
      PortugalNot in national immunization programme
      RomaniaNot in national immunization programme
      Slovakia20092+1
      Slovenia20113+1
      Spain20083+1
      Sweden20092+1
      Switzerland20062+1
      United Kingdom20062+1
      a National except Italy, Spain and Sweden, where the introduction was regional and Poland and Slovenia where the vaccine is recommended for high-risk groups.
      In addition, PCV7 vaccination of children also had an impact on non-invasive presentations of pneumococcal disease. For example, in the UK, hospitalizations for bacterial pneumonia and empyaema were reduced by 19% and 22%, respectively, 2 years after PCV7 implementation [
      • Koshy E
      • Murray J
      • Bottle A
      • Sharland M
      • Saxena S
      Impact of the seven-valent pneumococcal conjugate vaccination (PCV7) programme on childhood hospital admissions for bacterial pneumonia and empyema in England: national time-trends study, 1997–2008.
      ]. A retrospective interrupted time-series analysis of data from a large healthcare database in the USA (Nationwide Inpatient Sample) showed a 39% decrease in all-cause pneumonia hospital admission for children aged <2 years from before PCV7 introduction (1997–99) to after its introduction (2001–04) [
      • Grijalva CG
      • Nuorti JP
      • Arbogast PG
      • Martin SW
      • Edwards KM
      • Griffin MR
      Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis.
      ].
      In the background of substantial PCV7 supply shortages in 2001–03 and 2004, a step-wise reduction was reported in a retrospective study of acute otitis media visits in a private, non-profit health plan in the Boston area (Harvard Vanguard Medical Associates) that analysed data for children aged 2 months to 12 years between 1996 and 2004 [
      • Sox CM
      • Finkelstein JA
      • Yin R
      • Kleinman K
      • Lieu TA
      Trends in otitis media treatment failure and relapse.
      ,
      • Smith PJ
      • Nuorti JP
      • Singleton JA
      • Zhao Z
      • Wolter KM
      Effect of vaccine shortages on timeliness of pneumococcal conjugate vaccination: results from the 2001–2005 National Immunization Survey.
      ]. In this study there had been a reduction between the years 1996 and 1997 and the years 2001 and 2002, as the American Academy of Pediatrics and the CDC working group on acute otitis media guidelines published in 1999 recommendations for high-dose amoxicillin in children <2 years with uncomplicated otitis media and annual use of high-dose amoxicillin for the treatment of uncomplicated acute otitis media increased rapidly in the study setting between 1998 and 2000 [
      • Dowell SF
      • Butler JC
      • Giebink GS
      Acute otitis media: management and surveillance in an era of pneumococcal resistance. Drug-Resistant Streptococcus Pneumoniae Therapeutic Working Group.
      ]. There was another discrete step-wise fall in uncomplicated acute otitis media incidence between 2002 and 2004 [
      • Zhou F
      • Kyaw MH
      • Shefer A
      • Winston CA
      • Nuorti JP
      Health care utilization for pneumonia in young children after routine pneumococcal conjugate vaccine use in the United States.
      ]. Another retrospective analysis of a US insurance database (self-insured employers, including large private employers and state governments) in the USA (MarketScan) showed a 43% and 42% reduction in acute otitis media-related ambulatory visits and acute otitis media-related antibiotic prescriptions for children aged <2 years, respectively, comparing 2004 with the baseline 1997–99 [
      • Zhou F
      • Kyaw MH
      • Shefer A
      • Winston CA
      • Nuorti JP
      Health care utilization for pneumonia in young children after routine pneumococcal conjugate vaccine use in the United States.
      ], which was most marked between 2001 and 2002, followed by a linear decline from 2002 to 2004.
      In Greece, in an observational hospital-based study conducted over an 8-year period in children aged <14 years, the rates of otorrhoea visits per 10 000 emergency department visits was reduced by 38%, from 133 to 83, mainly through a reduction in the incidence of pneumococcal disease (48% decrease, from 25 to 13 per 10 000 emergency department visits) [
      • 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.
      ]. A similar impact on complicated otitis media has been reported in Italy and Sweden [
      • Durando P
      • Crovari P
      • Ansaldi F
      • et al.
      Universal childhood immunisation against Streptococcus pneumoniae: the five-year experience of Liguria Region, Italy.
      ,
      • Gisselsson-Solén M
      • Melhus Å
      • Hermansson A
      Pneumococcal vaccination in children at risk of developing recurrent acute otitis media – a randomized study.
      ].
      The impact on pneumococcal disease depends on the clinical presentation being measured, (Fig. 1). It is important to remember that a clinical presentation can be due to viral as well as bacterial infections. In addition, the disease can be caused by bacteria other than S. pneumoniae. Among disease caused by S. pneumoniae, vaccine serotypes account for a proportion that may depend on the particular clinical presentation of the pneumococcal disease. Consequently, the observed effectiveness of pneumococcal vaccination depends on the relative fraction of disease caused by vaccine serotype S. pneumoniae, the efficacy of PCV7 against vaccine serotype S. pneumoniae, the proportion of vaccine serotype pneumococcal supra-infections complicating a respiratory viral infection that can be avoided in pneumococcal conjugate vaccine immunized children [
      • Madhi SA
      • Klugman KP
      • The Vaccine Trialist Group
      A role for Streptococcus pneumoniae in virus-associated pneumonia.
      ], and the indirect (herd) impact from a generalized national immunization programme with PCV7 that can reduce the likelihood of transmission within the community.
      Figure thumbnail gr1
      FIG. 1Schematic representation of how, for a given type of clinical presentation, the fraction attributable to bacteria, Streptococcus pneumoniae and vaccine serotypes may vary. This phenomenon can explain how the impact on the different clinical presentations can vary also.

      Herd Effect and Replacement Disease

      PCV7 has also been shown to reduce asymptomatic nasopharyngeal carriage (NPC) of S. pneumoniae, which is a source for subsequent disease in the colonized person or of transmission to other susceptible individuals in the community. In 2009 in the Netherlands, 3 years after PCV7 had been introduced into the national immunization programmes, nasopharyngeal swabs were examined for pneumococcal carriage from three cohorts: healthy 11-month-old children who had received the three primary vaccinations; healthy 24-month-old children who had received also the final (booster) dose; and one parent of the older children. These were compared with historical control samples from a longitudinal randomised controlled trial that recruited 6-week-old children from July 2005 to February 2006 [
      • Spijkerman J
      • van Gils EJM
      • Veenhoven RH
      • et al.
      Carriage of Streptococcus pneumoniae 3 years after start of vaccination program, the Netherlands.
      ]. With respect to the vaccine serotypes, in the 11-month-old children there was an 86% (95% CI 77–91) reduction of VST-NPC, in 24-month old children (fully vaccinated) there was a 92% (95% CI 85–95) reduction, and in parents there was a 94% (95% CI 74–99) reduction. In another study, nasopharyngeal swabs were collected from consenting children ≤4 years old attending a paediatric outpatients department in a large UK teaching hospital from October to February in 2006/7, 2007/8 and 2008/9 [
      • Tocheva AS
      • Jefferies JM
      • Rubery H
      • et al.
      Declining serotype coverage of new pneumococcal conjugate vaccines relating to the carriage of Streptococcus pneumoniae in young children.
      ]. The results showed that, 2 years after the introduction of PCV7 in September 2006, there was a decrease in NPC of vaccine serotypes, particularly 6B (from 23.2 to 3.9%), 19F (from 13.5 to 1.0%) and 23F (from 8.7 to 2.9%). This was accompanied by an increase in the carriage of non-vaccine serotypes, particularly 19A (from 2.9 to 6.9%) and 6C (from 3.8 to 13.7%). In the Liguria Region in Italy, serotype 19A also emerged as a predominant non-vaccine serotype in NPC of children aged <5 years, over a 7-year period of vaccination with PCV7 that had very high uptake in the last 4 years [
      • Ansaldi F
      • de Florentiis D
      • Canepa P
      • et al.
      Carriage of Streptoccoccus pneumoniae 7 years after implementation of vaccination program in a population with very high and long-lasting coverage, Italy.
      ]. This phenomenon has also been reported in the Netherlands in a randomized controlled study and has been the subject of a literature review of observational studies [
      • Reinert R
      • Jacobs MR
      • Kaplan SL
      Pneumococcal disease caused by serotype 19A: review of the literature and implications for future vaccine development.
      ,
      • van Gils EJM
      • Veenhoven RH
      • Hak E
      • et al.
      Pneumococcal conjugate vaccination and nasopharyngeal acquisition of pneumococcal serotype 19A strains.
      ].
      PCV7 infant vaccination programmes have been shown to induce an indirect (herd) protection; for example, there was a reduction in vaccine-serotype IPD in the over 65-year-old population in the UK seen concurrently with the reduction in VST-IPD in the under 5-year-old population [
      • Miller E
      • Andrews NJ
      • Waight PA
      • Slack MP
      • George RC
      Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study.
      ]. A reduction of VST-IPD in all ages has been reported in two studies from Australia, six studies from Europe and two studies from the USA [
      • Pilishvili T
      • Lexau C
      • Farley MM
      • et al.
      Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine.
      ,
      • Rodenburg GD
      • de Greeff SC
      • Jansen AG
      • et al.
      Effects of pneumococcal conjugate vaccine 2 years after its introduction, the Netherlands.
      ,
      • Miller E
      • Andrews NJ
      • Waight PA
      • Slack MP
      • George RC
      Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study.
      ,
      • Fenoll A
      • Granizo JJ
      • Aguilar L
      • et al.
      Temporal trends of invasive Streptococcus pneumoniae serotypes and antimicrobial resistance patterns in Spain from 1979 to 2007.
      ,
      • Foster D
      • Walker AS
      • Paul J
      • et al.
      Reduction in invasive pneumococcal disease following implementation of the conjugate vaccine in the Oxfordshire region, England.
      ,
      • Guevara M
      • Barricarte A
      • Gil-Setas A
      • et al.
      Changing epidemiology of invasive pneumococcal disease following increased coverage with the heptavalent conjugate vaccine in Navarre, Spain.
      ,
      • Hanna JN
      • Humphreys JL
      • Murphy DM
      • Smith HV
      Invasive pneumococcal disease in non-Indigenous people in north Queensland, 2001–2009.
      ,
      • Lehmann D
      • Willis J
      • Moore HC
      • et al.
      The changing epidemiology of invasive pneumococcal disease in aboriginal and non-aboriginal western Australians from 1997 through 2007 and emergence of nonvaccine serotypes.
      ,
      • 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.
      ,
      • van Deursen AM
      • van Mens SP
      • Sanders EA
      • et al.
      Invasive pneumococcal disease and 7-valent pneumococcal conjugate vaccine, the Netherlands.
      ]. The reported reduction values range from 1.4% in the Netherlands to 93.5% in the USA, [
      • Pilishvili T
      • Lexau C
      • Farley MM
      • et al.
      Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine.
      ,
      • Rodenburg GD
      • de Greeff SC
      • Jansen AG
      • et al.
      Effects of pneumococcal conjugate vaccine 2 years after its introduction, the Netherlands.
      ]. The smallest all-age group reduction (1.4%) was reported for a period up to 2 years after the introduction of PCV in the national immunization programme in the Netherlands, but in another study reporting data up to 4 years after PCV7 introduction in the Netherlands the reduction was reported to be 53.6% (from 6.9 case per 100 000 to 3.2 cases per 100 000) [
      • Rodenburg GD
      • de Greeff SC
      • Jansen AG
      • et al.
      Effects of pneumococcal conjugate vaccine 2 years after its introduction, the Netherlands.
      ,
      • van Deursen AM
      • van Mens SP
      • Sanders EA
      • et al.
      Invasive pneumococcal disease and 7-valent pneumococcal conjugate vaccine, the Netherlands.
      ]. This illustrates the importance of knowing how long after vaccine introduction the assessment is carried out.
      However, while reducing vaccine-serotype disease, an important secondary effect of the PCV7 vaccination programme was found to be that of replacement disease caused by non-vaccine serotypes. In the UK, a significant rise in the incidence of IPD caused by serotypes 7F, 19A and 22F has been reported [
      • van der Linden M
      • Weiss S
      • Falkenhorst G
      • Siedler A
      • Imohl M
      • von Kries R
      Four years of universal pneumococcal conjugate infant vaccination in Germany: impact on incidence of invasive pneumococcal disease and serotype distribution in children.
      ]. In the USA, an increase in disease caused by antibiotic-resistant serotype 19A was reported [
      • PediSurv
      Surveillance of infectious diseases in children in Belgium [Surveillance des maladies infectieuses chez les enfants en Belgique].
      ,
      • Tocheva AS
      • Jefferies JM
      • Rubery H
      • et al.
      Declining serotype coverage of new pneumococcal conjugate vaccines relating to the carriage of Streptococcus pneumoniae in young children.
      ]. In a review of data on serotype replacement in disease after PCV7 vaccination it was reported that although in most populations there has been an increase in non-VST-IPD, in most cases this increase has been less than the reduction in VST-IPD, so resulting in a net reduction in all-type IPD [
      • Weinberger DM
      • Malley R
      • Lipsitch M
      Serotype replacement in disease after pneumococcal vaccination.
      ]. The authors suggest that the serotype replacement in nasopharyngeal carriage does not lead to a comparable serotype replacement in disease because of the lower invasiveness of the replacing serotypes in the nasopharynx. In comparing the incidence of IPD in the pre-vaccination and post-vaccination periods, disease surveillance systems must consistently note the source of clinical isolates (i.e. proportion of IPD from blood cultures of febrile children), be aware of changes in the frequency of IPD detection and reporting over time (i.e. active compared with passive reporting systems) and natural fluctuations in serotype-specific IPD incidence, obtain a sufficiently long period of follow-up, and follow the presence of immunodeficiencies and other co-morbidities with the clinical isolate. Furthermore, measured impact can depend upon vaccine uptake, include the rate of uptake and regional differences in vaccine uptake, as well as patterns of antibiotic use [
      • Weinberger DM
      • Malley R
      • Lipsitch M
      Serotype replacement in disease after pneumococcal vaccination.
      ].

      Impact of Childhood PCV13 Vaccination

      PCV13 has been introduced into national immunization programmes since 2010, and surveillance demonstrates that this vaccine has an additional impact, targeting the serotypes unique to PCV13, as well as continuing to protect against the PCV7 serotypes. In the UK, PCV13 was introduced nationwide in transition from PCV7 (i.e. as the next vaccine for any dose in the paediatric pneumococcal conjugate vaccination schedule); however, there was no catch-up vaccination programme for older children who were already fully vaccinated with PCV7. The first published data from the UK, covering the transition period between the two vaccines, showed that among the 166 IPD cases in PCV13-eligible children reported by July 2011, the vaccine effectiveness was 78% (95% CI–18–96) for two doses administered to children aged <12 months and 73% (95% CI 29–90) for one dose (aged ≥12 months) [
      • Miller E
      • Andrews NJ
      • Waight PA
      • Slack MP
      • George RC
      Effectiveness of the new serotypes in the 13-valent pneumococcal conjugate vaccine.
      ]. Importantly, IPD caused by the PCV7 non-vaccine serotypes 7F and 19A has been offset, as the vaccine effectiveness for at least one dose for 19A and 7F IPD was 70% (95% CI 10–90) and 76% (95% CI 21–93), respectively. Active surveillance of both carried pneumococci in young children and the serotypes causing IPD is critical to inform new vaccine development and national immunization policies.

      Remaining Burden of IPD

      The burden of IPD has been substantially reduced due to the impact of PCV7 on the incidence of VST-IPD, and the remaining disease burden can be accounted for, to a large extent, by the serotypes targeted by the higher-order pneumococcal conjugate vaccines [
      • Pilishvili T
      • Lexau C
      • Farley MM
      • et al.
      Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine.
      ,
      • Bettinger JA
      • Scheifele DW
      • Kellner JD
      • et al.
      The effect of routine vaccination on invasive pneumococcal infections in Canadian children, Immunization Monitoring Program, Active 2000–2007.
      ,
      • Isaacman DJ
      • McIntosh ED
      • Reinert RR
      Burden of invasive pneumococcal disease and serotype distribution among Streptococcus pneumoniae isolates in young children in Europe: impact of the 7-valent pneumococcal conjugate vaccine and considerations for future conjugate vaccines.
      ,
      • Ingels H
      • Rasmussen J
      • Andersen PH
      • et al.
      Impact of pneumococcal vaccination in Denmark during the first 3 years after PCV introduction in the childhood immunization programme.
      ]. With the widespread introduction of PCV13 we can expect to see further reductions in the incidence of IPD through the non-PCV7 serotypes present in PCV13.
      Even after the introduction of paediatric PCV programmes, the incidence of IPD still has a characteristic U-shaped distribution, with the incidence being higher in children <5 years, then decreasing in older children, adolescents and young adults and finally increasing again in those aged >45–50 years, although the incidence at the two extremes of age has decreased. Data from a passive surveillance system in Europe, which probably underestimates the disease burden, showed that in 2009, the highest incidence of IPD was reported for those aged 65+ (9.84 per 100 000) and the next highest was in children <5 years (6.57 per 100 000) [
      • European Centre for Disease Prevention and Control
      ]. In 2009, in the USA the rate of IPD (per 100 000) was greatest in children under 5 (<1 year: 34.2; 1 year: 26.6; 2–4 years: 13.1) and in adults aged 50+ (50–64 years: 18.8; 65+: 36.4) [
      • Centers for Disease Control and Prevention
      ]. As childhood immunization with PCV7 has had an impact (both direct and indirect) on the burden of invasive disease across a number of age groups, it is now anticipated that PCV13 will be effective against all PCV13 vaccine-serotype serotypes in non-immunized age groups as has been seen for PCV7 vaccine-serotype disease.

      What Can We Expect from Vaccinating Adults with PCV13?

      In October 2011 PCV13 was approved for active immunization for the prevention of invasive disease caused by S. pneumoniae in adults aged 50 years and older in Europe. On December 30, 2011, under their accelerated approval regulation, the FDA approved PCV13 for prevention of pneumonia and invasive disease caused by PCV13 serotypes among adults aged 50 years and older.
      The clinical trials for the licensure of PCV13 in children used a correlate of protection established by the WHO, an ‘immunogenicity bridge’ for paediatric licensure based on an IgG threshold of 0.35 μg/mL, with an outcome of non-inferiority of the immune response, compared with PCV7, assessed after the primary series [
      • Gruber WC
      • Scott DA
      • Emini EA
      Development and clinical evaluation of Prevnar 13, a 13-valent pneumocococcal CRM197 conjugate vaccine.
      ]. For the clinical trials with PCV13 in adults, a serotype-specific OPA was used as an immunological basis for licensure, as compared with the licensed 23-valent pneumococcal polysaccharide vaccine PPV23 vaccine. OPA geometric mean titres (GMTs) are expressed as the reciprocal of the highest serum dilution that reduces survival of the pneumococci by at least 50%. Pivotal clinical trials for PCV13 demonstrated the non-inferiority of functional OPA antibody responses 1-month after vaccination for the 12 serotypes that are common with PPV23 (1, 3,4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F). The response to serotype 6A, which is unique to PCV13, was assessed by demonstrating a four-fold increase from pre-vaccination levels in the specific OPA titre.
      As part of the accelerated approval regulation, a post-licensure, randomized, placebo-controlled clinical trial is currently underway in the Netherlands to assess the efficacy of PCV13 in the prevention of a first episode of VST pneumococcal CAP in community-dwelling adults aged ≥65 years [
      • Hak E
      • Grobbee DE
      • Sanders EA
      • et al.
      Rationale and design of CAPITA: a RCT of 13-valent conjugated pneumococcal vaccine efficacy among older adults.
      ]. Although not part of the clinical programme for PCV13 in adults, PCV7 efficacy in immunocompromised subjects has been demonstrated in a double-blind, randomized (1 : 1), placebo-controlled clinical efficacy trial in Malawi in a population (n = 496) who had recovered from documented IPD and that included 88% HIV-infected individuals. They received two doses of PCV7 given 4 weeks apart [
      • French N
      • Gordon SB
      • Mwalukomo T
      • et al.
      A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults.
      ]. A vaccine efficacy of 74% (95% CI 30–90) was reported against a further episode of pneumococcal infection by VST serotypes or serotype 6A among HIV-infected subjects [and, for all subjects, there was an efficacy of 73% (95% CI 23–89)]. In a subgroup of 220 patients who were severely immunocompromised (CD4+ cell count <200 cells/mm3 at baseline), the vaccine efficacy was 86% (95% CI 41–97).
      The plain polysaccharide vaccine, PPV23, is effective against IPD in younger adults, although efficacy in elderly subjects or in those with underlying co-morbidities, the duration of protection and guidelines for revaccination, and the impact on all-cause pneumonia have not been clearly established [
      • Moberley SA
      • Holden J
      • Tatham DP
      • Andrews RM
      Vaccines for preventing pneumococcal infection in adults.
      ,
      • Pletz MW
      • Maus U
      • Krug N
      • Welte T
      • Lode H
      Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species.
      ]. The immunogenicity and safety of PCV13 have been demonstrated in adults aged 50 years and older, including those previously vaccinated with a pneumococcal polysaccharide vaccine [
      • European Medicines Agency
      Assessment report-Prevenar 13 pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) - Procedure No.: EMEA/H/C/001104/II/0028.
      ]. PCV13 may be administered concomitantly with the seasonal trivalent inactivated influenza vaccine. Regardless of previous pneumococcal vaccination status, if the use of 23-valent polysaccharide is considered appropriate, PCV13 should be given first [
      • European Medicines Agency
      Assessment report-Prevenar 13 pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) - Procedure No.: EMEA/H/C/001104/II/0028.
      ]. PCV13 induces an immune response that is associated with immunological memory, while plain polysaccharide vaccine does not. In subjects aged 60–64 years, the duration of the immunological memory provided by PCV13 has been demonstrated at 3–4 years after primary vaccination, based on response to revaccination with PCV13 or subsequent vaccination with PPV23 [
      • European Medicines Agency
      Assessment report-Prevenar 13 pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) - Procedure No.: EMEA/H/C/001104/II/0028.
      ].

      Conclusions

      The burden of pneumococcal disease remains high, despite effective childhood vaccination with PCVs. In 2008 the WHO stated: ‘there is a need for more efficacious conjugated vaccines or other types of vaccines covering the majority of the pneumococcal serotypes that cause serious disease in older children and adults worldwide and that frequently are also responsible for resistance to commonly used antimicrobial drugs. WHO supports the ongoing efforts to develop such products’ [
      • Ansaldi F
      • de Florentiis D
      • Canepa P
      • et al.
      Carriage of Streptoccoccus pneumoniae 7 years after implementation of vaccination program in a population with very high and long-lasting coverage, Italy.
      ,
      • McIntosh ED
      • Reinert RR
      Global prevailing and emerging pediatric pneumococcal serotypes.
      ,
      • World Health Organization
      23-valent pneumococcal polysaccharide vaccine. WHO position paper.
      ]. Since the elderly population remains at risk, the growing elderly population throughout the world will therefore amplify the burden. Although effective antibiotics are available, global mortality rates attributable to S. pneumoniae disease have not changed significantly over many decades. Novel immunization strategies remain the only practical means to reduce significantly the global mortality and morbidity due to S. pneumoniae in adults.

      Transparency Declaration

      P. Durando has participated in speakers’ bureaus and advisory board meetings sponsored by GSK, Novartis, Pfizer and Sanofi Pasteur; he has received research funding as principal investigator or co-investigator from Crucell Berna, Novartis, GSK, Pfizer and Sanofi Pasteur. S.N. Faust ………???. M. Fletcher is an employee of Pfizer, the manufacturer of Prevenar and Prevenar 13. P. Krizova has been a speaker and consultant at advisory boards for Novartis, GSK, Pfizer, and Baxter. A. Torres has been a speaker for Bayer, Astra Zeneca and Pfizer and a consultant at advisory boards for Cerexa, GSK, and Theravance. T. Welte has participated in advisory boards for AstraZeneca, GSK, Novartis and Pfizer; and he has received fees for lectures from AstraZeneca, GSK, MSD, Novartis and Pfizer; he has received research grants from Novartis.
      S.N. Faust acts as chief or principal investigator for clinical trials conducted on behalf of University Hospital Southampton NHS Foundation Trust and the University of Southampton, sponsored by vaccine manufacturers but receives no personal payments from them. S.N. Faust have participated in advisory boards and conferences for vaccine manufacturers but receives no personal payments for this work. S.N. Faust had received financial assistance from vaccine manufacturers to attend conferences. All grants and honoraria are paid into accounts at University Hospital Southampton NHS Foundation Trust or the University of Southampton.

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