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1.  Recommendation for use of the newly introduced pneumococcal protein conjugate vaccines in Korea 
Korean Journal of Pediatrics  2011;54(4):146-151.
Streptococcus pneumoniae remains a leading cause of invasive infections including bacteremia and meningitis, as well as mucosal infections such as otitis media and pneumonia among children and adults. The 7-valent pneumococcal conjugate vaccine (PCV7) was licensed for use among infants and young children in many countries including Korea. The routine use of PCV7 has resulted in a decreased incidence of invasive pneumococcal disease (IPD) by the vaccine serotypes among the vaccinees and substantial declines in IPD among unvaccinated populations such as older children and adults as well. In addition, there are increasing evidences to suggest that routine immunization with PCV7 is changing the epidemiology of pneumococcal diseases such as serotype distribution of IPD, nasopharyngeal colonization, and antibiotic resistance patterns. In contrast, there is an increase in the number of IPDs caused by nonvaccine serotypes, though it is much smaller than overall declines of vaccine serotype diseases. Several vaccines containing additional serotypes have been developed and tested clinically in order to expand the range of serotypes of Streptococcus pneumoniae. Recently two new pneumococcal protein conjugate vaccines, 10-valent pneumococcal conjugate vaccine (PCV10) and 13-valent pneumococcal conjugate vaccine (PCV13), have been approved for use in several countries including Korea. This report summarizes the recommendations approved by the Committee on Infectious Diseases, the Korean Pediatric Society.
doi:10.3345/kjp.2011.54.4.146
PMCID: PMC3127147  PMID: 21738547
Streptococcus pneumoniae; Pneumococcal conjugate vaccine; Serotype
2.  Potential cost-effectiveness and benefit-cost ratios of adult pneumococcal vaccination in Germany 
Background
Invasive (IPD, defined as detection of pneumococci in sterile body fluids like meningitis or bacteremic pneumonia) and non-invasive Streptococcus pneumoniae infections (i.e. non-bacteremic pneumonia, otitis media) in adults are associated with substantial morbidity, mortality and costs. In Germany, Pneumococcal polysaccharide vaccination (PPV23) is recommended for all persons >60 years and for defined risk groups (age 5–59). The aim of this model was to estimate the potential cost-effectiveness and benefit-cost ratios of the adult vaccination program (18 years and older), considering the launch of the pneumococcal conjugate vaccine for adults (PCV13).
Methods
A cross-sectional steady state Markov model was developed to estimate the outcomes of PCV13, PPV23 vaccination schemes and ‘no vaccination’. Conservative assumptions were made if no data were available for PCV13 and PPV23 respectively. The effectiveness of individual pneumococcal vaccination in adults was adjusted for expected indirect effects due to the vaccination in infants. Data on incidences, effectiveness and costs were derived from scientific literature and publicly available databases. All resources used are indicated. Benefit-cost ratios and cost-effectiveness were evaluated from the perspective of the German Statutory Health Insurance as well as from social perspective.
Results
Under the assumption that PCV13 has a comparable effectiveness to PCV7, a vaccination program with PCV13 revealed the potential to avoid a greater number of yearly cases and deaths in IPD and pneumonia in Germany compared to PPV23. For PCV13, the costs were shown to be overcompensated by monetary savings resulting from reduction in the use of health care services. These results would render the switch from PPV23 to PCV13 as a dominant strategy compared to PPV23 and ‘no vaccination’. Given the correctness of the underlying assumptions every Euro spent on the PCV13 vaccination scheme yields savings of 2.09 € (social perspective: 2.16 €) compared to PPV23 and 1.27 € (social perspective: 1.32 €) compared to ‘no vaccination’, respectively.
Conclusions
Results of the model indicate that the health economic benefit of immunizing adults with PCV13 can be expected to outperform the sole use of PPV23, if the effectiveness of PCV13 is comparable to the effectiveness of PCV7.
doi:10.1186/2191-1991-2-4
PMCID: PMC3463422  PMID: 22828176
Cost; Effectiveness; Pneumococcal polysaccharide vaccine; Pneumococcal conjugate vaccine; Adult; Benefit-cost
3.  International Circumpolar Surveillance System for Invasive Pneumococcal Disease, 1999–2005 
Emerging Infectious Diseases  2008;14(1):25-33.
Disease rates are high among indigenous persons in Arctic countries, and PCV7 has resulted in decreased rates in North American children.
The International Circumpolar Surveillance System is a population-based surveillance network for invasive bacterial disease in the Arctic. The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced for routine infant vaccination in Alaska (2001), northern Canada (2002–2006), and Norway (2006). Data for invasive pneumococcal disease (IPD) were analyzed to identify clinical findings, disease rates, serotype distribution, and antimicrobial drug susceptibility; 11,244 IPD cases were reported. Pneumonia and bacteremia were common clinical findings. Rates of IPD among indigenous persons in Alaska and northern Canada were 43 and 38 cases per 100,000 population, respectively. Rates in children <2 years of age ranged from 21 to 153 cases per 100,000 population. In Alaska and northern Canada, IPD rates in children <2 years of age caused by PCV7 serotypes decreased by >80% after routine vaccination. IPD rates are high among indigenous persons and children in Arctic countries. After vaccine introduction, IPD caused by non-PCV7 serotypes increased in Alaska.
doi:10.3201/eid1401.071315
PMCID: PMC2600171  PMID: 18258073
Streptococcus pneumoniae; invasive pneumococcal disease; IPD; surveillance; PCV7; serotype replacement; indigenous; Alaska Native; circumpolar; arctic; research
4.  Pediatric Invasive Pneumococcal Disease in the United States in the Era of Pneumococcal Conjugate Vaccines 
Clinical Microbiology Reviews  2012;25(3):409-419.
Summary: Invasive infections caused by Streptococcus pneumoniae continue to be a major cause of morbidity and mortality worldwide, especially in children under 5 years of age. In the United States, 90% of invasive pneumococcal infections in children are caused by 13 serotypes of S. pneumoniae. The licensure (in 2000) and subsequent widespread use of a heptavalent pneumococcal conjugate vaccine (PCV7) have had a significant impact on decreasing the incidence of serious invasive pneumococcal disease (IPD) in all age groups, especially in children under 2 years of age. However, the emergence of replacement non-PCV7 serotypes, especially serotype 19A, has resulted in an increase in the incidence of serious and invasive infections. In 2010, a 13-valent PCV was licensed in the United States. However, the impact that this vaccine will have on IPD remains to be seen. The objectives of this review are to discuss the epidemiology of serious and invasive pneumococcal infections in the United States in the PCV era and to review some of the pneumococcal vaccines that are in development.
doi:10.1128/CMR.00018-12
PMCID: PMC3416489  PMID: 22763632
5.  PspA Family Distribution, unlike Capsular Serotype, Remains Unaltered following Introduction of the Heptavalent Pneumococcal Conjugate Vaccine 
Pneumococcal conjugate vaccines (PCVs) are recommended for the prevention of invasive pneumococcal disease (IPD) in young children. Since the introduction of the heptavalent pneumococcal vaccine (PCV7) in 2000, IPD caused by serotypes in the vaccine has almost been eliminated, and previously uncommon capsular serotypes now cause most cases of pediatric IPD in the United States. One way to protect against these strains would be to add cross-reactive protein antigens to new vaccines. One such protein is pneumococcal surface protein A (PspA). Prior to 2000, PspA families 1 and 2 were expressed by 94% of isolates. Because PCV7 vaccine pressure has resulted in IPD caused by capsular serotypes that were previously uncommon and unstudied for PspA expression, it was possible that many of the new strains expressed different PspA antigens or even lacked PspA. Of 157 pediatric invasive pneumococcal isolates collected at a large pediatric hospital in Alabama between 2002 and 2010, only 60.5% had capsular serotypes included in PCV13, which came into general use in Alabama after our strains were collected. These isolates included 17 serotypes that were not covered by PCV13. Nonetheless, pneumococcal capsular serotype replacement was not associated with changes in PspA expression; 96% of strains in this collection expressed PspA family 1 or 2. Continued surveillance will be critical to vaccine strategies to further reduce IPD.
doi:10.1128/CVI.05671-11
PMCID: PMC3370451  PMID: 22539473
6.  Invasive Pneumococcal Disease in Infants Younger Than 90 Days Before and After Introduction of PCV7 
Pediatrics  2013;132(1):e17-e24.
BACKGROUND:
Introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) changed the epidemiology of invasive pneumococcal disease (IPD). We evaluated the changes that occurred after PCV7 introduction among Utah infants aged 1 to 90 days, too young to be fully immunized.
METHODS:
We identified children <18 years with culture-confirmed IPD from 1997–2010. We analyzed demographic, clinical, and serotype data for infants aged 1–90 days. The pre– and post–vaccine introduction periods spanned 1997–2000 and 2001–2010, respectively.
RESULTS:
Of 513 children with IPD, 36 were 1 to 90 days and accounted for 7% of IPD cases in both the pre– and post–vaccine introduction period. The pre–vaccine IPD incidence rate was 5.0 per 100 000 live births, and was unchanged in the post–vaccine introduction period. IPD caused by PCV7 serotypes decreased by 74% (from 2.2 to 0.58 per 100 000), whereas non-vaccine serotype IPD increased by 57% (from 2.8 to 4.4 per 100 000). Sixteen infants (44%) required intensive care, and 3 (8%) died. Bacteremia without focus (56%) and meningitis (44%) were the predominant syndromes in the pre– and post–vaccine introduction periods, respectively. In the post–vaccine introduction period, serotype 7F was the most common serotype among infants and was responsible for 50% of meningitis.
CONCLUSIONS:
The incidence of IPD in Utah infants aged 1 to 90 days caused by PCV7 serotypes decreased after PCV7 introduction, but overall incidence was unchanged. In the post–vaccine introduction period, serotype 7F predominated in this age group and was associated with meningitis.
doi:10.1542/peds.2012-3900
PMCID: PMC3691535  PMID: 23733800
invasive pneumococcal disease; Streptococcus pneumoniae; infant; pneumococcal conjugate vaccine
7.  Clinical Implications of Pneumococcal Serotypes: Invasive Disease Potential, Clinical Presentations, and Antibiotic Resistance 
Streptococcus pneumoniae can asymptomatically colonize the nasopharynx and cause a diverse range of illnesses. This clinical spectrum from colonization to invasive pneumococcal disease (IPD) appears to depend on the pneumococcal capsular serotype rather than the genetic background. According to a literature review, serotypes 1, 4, 5, 7F, 8, 12F, 14, 18C, and 19A are more likely to cause IPD. Although serotypes 1 and 19A are the predominant causes of invasive pneumococcal pneumonia, serotype 14 remains one of the most common etiologic agents of non-bacteremic pneumonia in adults, even after 7-valent pneumococcal conjugate vaccine (PCV7) introduction. Serotypes 1, 3, and 19A pneumococci are likely to cause empyema and hemolytic uremic syndrome. Serotype 1 pneumococcal meningitis is prevalent in the African meningitis belt, with a high fatality rate. In contrast to the capsule type, genotype is more closely associated with antibiotic resistance. CC320/271 strains expressing serotype 19A are multidrug-resistant (MDR) and prevalent worldwide in the era of PCV7. Several clones of MDR serotype 6C pneumococci emerged, and a MDR 6D clone (ST282) has been identified in Korea. Since the pneumococcal epidemiology of capsule types varies geographically and temporally, a nationwide serosurveillance system is vital to establishing appropriate vaccination strategies for each country.
doi:10.3346/jkms.2013.28.1.4
PMCID: PMC3546102  PMID: 23341706
Streptococcus pneumoniae; Polysaccharides, Bacterial; Bacterial Capsules; Serotyping; Pneumococcal Infections
8.  Antimicrobial Resistance among Isolates Causing Invasive Pneumococcal Disease before and after Licensure of Heptavalent Conjugate Pneumococcal Vaccine 
PLoS ONE  2009;4(6):e5965.
Background
The impact of the pneumococcal conjugate vaccine (PCV-7) on antibiotic resistance among pneumococcal strains causing invasive pneumococcal disease (IPD) has varied in different locales in the United States. We assessed trends in IPD including trends for IPD caused by penicillin non-susceptible strains before and after licensure of PCV-7 and the impact of the 2008 susceptibility breakpoints for penicillin on the epidemiology of resistance.
Methodology/Principal Findings
We performed a retrospective review of IPD cases at Morgan Stanley Children's Hospital of NewYork-Presbyterian, Columbia University Medical Center. Subjects were ≤18 years of age with Streptococcus pneumoniae isolated from sterile body sites from January 1995–December 2006. The rate of IPD from 1995–1999 versus 2002–2006 significantly decreased from 4.1 (CI95 3.4, 4.8) to 1.7 (CI95 1.3, 2.2) per 1,000 admissions. Using the breakpoints in place during the study period, the proportion of penicillin non-susceptible strains increased from 27% to 49% in the pre- vs. post-PCV-7 era, respectively (p = 0.001), although the rate of IPD caused by non-susceptible strains did not change from 1995–1999 (1.1 per 1,000 admissions, CI95 0.8, 1.5) when compared with 2002–2006 (0.8 per 1,000 admissions, CI95 0.6, 1.2). In the multivariate logistic regression model controlling for the effects of age, strains causing IPD in the post-PCV-7 era were significantly more likely to be penicillin non-susceptible compared with strains in the pre-PCV-7 era (OR 2.46, CI95 1.37, 4.40). However, using the 2008 breakpoints for penicillin, only 8% of strains were non-susceptible in the post-PCV-7 era.
Conclusions/Significance
To date, there are few reports that document an increase in the relative proportion of penicillin non-susceptible strains of pneumococci causing IPD following the introduction of PCV-7. Active surveillance of pneumococcal serotypes and antibiotic resistance using the new penicillin breakpoints is imperative to assess potential changes in the epidemiology of IPD.
doi:10.1371/journal.pone.0005965
PMCID: PMC2694368  PMID: 19536335
9.  Systematic Review of the Indirect Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Pneumococcal Disease and Colonization 
The Pediatric Infectious Disease Journal  2013;33(Suppl 2 Optimum Dosing of Pneumococcal Conjugate Vaccine For Infants 0 A Landscape Analysis of Evidence Supportin g Different Schedules):S161-S171.
Background:
To aid decision making for pneumococcal conjugate vaccine (PCV) use in infant national immunization programs, we summarized the indirect effects of PCV on clinical outcomes among nontargeted age groups.
Methods:
We systematically reviewed the English literature on infant PCV dosing schedules published from 1994 to 2010 (with ad hoc addition of 2011 articles) for outcomes on children >5 years of age and adults including vaccine-type nasopharyngeal carriage (VT-NP), vaccine-type invasive pneumococcal disease (VT-IPD) and syndromic pneumonia.
Results:
Of 12,980 citations reviewed, we identified 21 VT-IPD, 6 VT-NP and 9 pneumonia studies. Of these 36, 21 (58%) included 3 primary doses plus PCV or pneumococcal polysaccharide vaccine (PPV23) booster schedule (3+1 or 3+PPV23), 5 (14%) 3+0, 9 (25%) 2+1 and 1 (3%) 2+0. Most (95%) were PCV7 studies. Among observational VT-IPD studies, all schedules (2+1, 3+0 and 3+1) demonstrated reductions in incidence among young adult groups. Among syndromic pneumonia observational studies (2+1, 3+0 and 3+1), only 3+1 schedules showed significant indirect impact. Of 2 VT-NP controlled trials (3+0 and 3+1) and 3 VT-NP observational studies (2+1, 3+1 and 3+PPV23), 3+1 and 3+PPV23 schedules showed significant indirect effect. The 1 study to directly compare between schedules was a VT-NP study (2+0 vs. 2+1), which found no indirect effect on older siblings and parents of vaccinated children with either schedule.
Conclusions:
Indirect benefit of a 3+1 infant PCV dosing schedule has been demonstrated for VT-IPD, VT-NP and syndromic pneumonia; 2+1 and 3+0 schedules have demonstrated indirect effect only for VT-IPD. The choice of optimal infant PCV schedule is limited by data paucity on indirect effects, especially a lack of head-to-head studies and studies of PCV10 and PCV13.
doi:10.1097/INF.0000000000000084
PMCID: PMC3940524  PMID: 24336058
pneumococcal conjugate vaccine; nasopharyngeal carriage; pneumonia; pneumococcal disease; indirect effects
10.  A Pneumococcal Carriage Study in Danish Pre-school Children before the Introduction of Pneumococcal Conjugate Vaccination 
We present data on pneumococcal carriage before the introduction of the heptavalent-pneumococcal conjugated vaccine (PCV7) in Denmark. In the pre-PCV7 period, the incidence of invasive pneumococcal disease (IPD) among children younger than 5 years was approximately 25 per 100.000 population, with the highest incidence rates observed in children younger than 2 years of age. The study included 437 children aged 12-72 months attending day care centres (DCC) and was conducted during 48 months. In total, 56% (n=247) of children were pneumococcal carriers with the highest prevalence in children aged 12–23 months (69%), the proportion significantly declining with increasing age. PCV7 serotypes accounted for 33%, PCV10 for 34%, and PCV13 for 57% of all carried isolates. The proportion of serotypes included in the three conjugate vaccines was higher among IPD isolates compared to carrier isolates (range 35– 90%). We found that the frequency of carriage was high among Danish pre-school children attending DCC and serotypes were not frequently covered by PCV7 in the pre-PCV7 period.
doi:10.2174/1874285801206010040
PMCID: PMC3355352  PMID: 22611459
Children; nasopharyngeal carriage; Streptococcus pneumoniae; serotypes; vaccine.
11.  Impact of pneumococcal vaccines use on invasive pneumococcal disease in Nunavik (Quebec) from 1997 to 2010 
International Journal of Circumpolar Health  2014;73:10.3402/ijch.v73.22691.
Background
In 2000, an outbreak of severe pneumonia caused by a virulent clone of serotype 1 Streptococcus pneumoniae was detected in the Nunavik region of Quebec. A mass immunization campaign was implemented in the spring of 2002, targeting persons ≥5 years of age and using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). At the same time, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the routine immunization programme of infants, with catch-up for children up to 4 years of age.
Objectives
To describe the epidemiology of invasive pneumococcal disease (IPD) in relation to PPSV23 and PCV7 use.
Study design and methods
Retrospective analysis of IPD cases identified by the Quebec public health laboratory during the period 1997–2010.
Results
A total of 82 IPD cases were identified during the study period. In adults, serotype 1 incidence decreased following the 2002 PPSV23 mass campaign but breakthrough cases continued to occur. Following PCV7 use in children, there was a decrease in the incidence of vaccine-type IPD and replacement by other serotypes in adults. In children, a marked decrease in the annual incidence of serotypes included in PCV7 was observed following PCV7 introduction: 162/100,000 in 1997–2001 vs. 10/100,000 in 2004–2010 (p<0.01). Concomitantly, the incidence of IPD caused by serotypes not included in PCV7 increased from 29/100,000 to 109/100,000 (p=0.11).
Conclusion
The mass immunization campaign using the PPSV23 in 2002 and the introduction of PCV7 for the routine immunization of infants induced important modifications in the epidemiology of IPD. IPD rates in Nunavik remain much higher than in the southern part of the province both in children and adults. More effective pneumococcal vaccines are needed to eliminate geographic disparities in IPD risk.
doi:10.3402/ijch.v73.22691
PMCID: PMC3896896  PMID: 24455492
immunization; epidemiology; Streptococcus pneumonia; paediatric vaccine; Inuit
12.  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(1):e00309-10.
A seven-valent pneumococcal conjugate vaccine (PCV7) introduced in the United States in 2000 has been shown to reduce invasive pneumococcal disease (IPD) in both vaccinated children and adults through induction of herd immunity. We assessed the impact of infant immunization on pneumococcal pneumonia hospitalizations and mortality in all age groups using Health Care Utilization Project State Inpatient Databases (SID) for 1996 to 2006 from 10 states; SID contain 100% samples of ICD9-coded hospitalization data for the selected states. Compared to a 1996–1997 through 1998–1999 baseline, by the 2005–2006 season, both IPD and pneumococcal pneumonia hospitalizations and deaths had decreased substantially in all age groups, including a 47% (95% confidence interval [CI], 38 to 54%) reduction in nonbacteremic pneumococcal pneumonia (ICD9 code 481 with no codes indicating IPD) in infants <2 years old and a 54% reduction (CI, 53 to 56%) in adults ≥65 years of age. A model developed to calculate the total burden of pneumococcal pneumonia prevented by infant PCV7 vaccination in the United States from 2000 to 2006 estimated a reduction of 788,838 (CI, 695,406 to 875,476) hospitalizations for pneumococcal pneumonia. Ninety percent of the reduction in model-attributed pneumococcal pneumonia hospitalizations occurred through herd immunity among adults 18 years old and older; similar proportions were found in pneumococcal disease mortality prevented by the vaccine. In the first seasons after PCV introduction, when there were substantial state differences in coverage among <5-year-olds, states with greater coverage had significantly fewer influenza-associated pneumonia hospitalizations among children, suggesting that PCV7 use also reduces influenza-attributable pneumonia hospitalizations.
IMPORTANCE
Pneumonia is the world’s leading cause of death in children and the leading infectious cause of death among U.S. adults 65 years old and older. Pneumococcal conjugate vaccination of infants has previously been shown to reduce invasive pneumococcal disease (IPD) among seniors through prevention of pneumococcal transmission from infants to adults (herd immunity). Our analysis documents a significant vaccine-associated reduction not only in IPD but also in pneumococcal pneumonia hospitalizations and inpatient mortality rates among both vaccinated children and unvaccinated adults. We estimate that fully 90% of the reduction in the pneumonia hospitalization burden occurred among adults. Moreover, states that more rapidly introduced their infant pneumococcal immunization programs had greater reductions in influenza-associated pneumonia hospitalization of children, presumably because the vaccine acts to prevent the pneumococcal pneumonia that frequently follows influenza virus infection. Our results indicate that seven-valent pneumococcal conjugate vaccine use has yielded far greater benefits through herd immunity than have previously been recognized.
doi:10.1128/mBio.00309-10
PMCID: PMC3025524  PMID: 21264063
13.  Cost-effectiveness of 2 + 1 dosing of 13-valent and 10-valent pneumococcal conjugate vaccines in Canada 
BMC Infectious Diseases  2012;12:101.
Background
Thirteen-valent pneumococcal conjugate vaccine (PCV13) and 10-valent pneumococcal conjugate vaccine (PCV10) are two recently approved vaccines for the active immunization against Streptococcus pneumoniae causing invasive pneumococcal disease in infants and children. PCV13 offers broader protection against Streptococcus pneumoniae; however, PCV10 offers potential protection against non-typeable Haemophilus influenza (NTHi). We examined public health and economic impacts of a PCV10 and PCV13 pediatric national immunization programs (NIPs) in Canada.
Methods
A decision-analytic model was developed to examine the costs and outcomes associated with PCV10 and PCV13 pediatric NIPs. The model followed individuals over the remainder of their lifetime. Recent disease incidence, serotype coverage, population data, percent vaccinated, costs, and utilities were obtained from the published literature. Direct and indirect effects were derived from 7-valent pneumococcal vaccine. Additional direct effect of 4% was attributed to PCV10 for moderate to severe acute otitis media to account for potential NTHi benefit. Annual number of disease cases and costs (2010 Canadian dollars) were presented.
Results
In Canada, PCV13 was estimated to prevent more cases of disease (49,340 when considering both direct and indirect effects and 7,466 when considering direct effects only) than PCV10. This translated to population gains of 258 to 13,828 more quality-adjusted life-years when vaccinating with PCV13 versus PCV10. Annual direct medical costs (including the cost of vaccination) were estimated to be reduced by $5.7 million to $132.8 million when vaccinating with PCV13. Thus, PCV13 dominated PCV10, and sensitivity analyses showed PCV13 to always be dominant or cost-effective versus PCV10.
Conclusions
Considering the epidemiology of pneumococcal disease in Canada, PCV13 is shown to be a cost-saving immunization program because it provides substantial public health and economic benefits relative to PCV10.
doi:10.1186/1471-2334-12-101
PMCID: PMC3532329  PMID: 22530841
Vaccine; Cost-effectiveness; Pneumococcal conjugate vaccine; Pneumococcal disease
14.  Clonal Distribution of Common Pneumococcal Serotypes Not Included in the 7-Valent Conjugate Vaccine (PCV7): Marked Differences between Two Ethnic Populations in Southern Israel 
Journal of Clinical Microbiology  2012;50(11):3472-3477.
This study aimed to compare the clonal distribution of common pneumococcal strains not included in the 7-valent pneumococcal conjugate vaccine (PCV7) that were isolated from cases of acute otitis media (AOM) and invasive pneumococcal disease (IPD) in two distinct ethnic populations in southern Israel during the decade (1999 to 2008) preceding PCV7 implementation. Isolates recovered from Jewish and Bedouin children <5 years old were characterized by antibiotic resistance and molecular epidemiology using pulsed-field gel electrophoresis and multilocus sequence typing. Of 5,236 AOM and 425 IPD isolates, 43% and 57% were from Jewish and Bedouin children, respectively. PCV7 accounted for 54% and 45% of the AOM and IPD episodes, respectively. Eleven major non-PCV7 serotypes (1, 3, 5, 6A, 7F, 12F, 15B/C, 19A, 21, 33F, and 35B) constituted 31% and 42% of the AOM and IPD episodes, respectively. The clonal distributions of the 11 non-PCV7 serotypes and their antibiotic susceptibilities were significantly different among the two ethnic populations in both the AOM and IPD groups. About half of the AOM and IPD cases resulted from non-PCV7 pneumococci, even before PCV7 implementation. The significant differences between the two ethnic populations suggest that lifestyle and microenvironment are major determinants in the clonal distribution of disease-causing pneumococci. Post-PCV7 surveillance is important in understanding non-PCV7 clonal expansion in the two distinct populations.
doi:10.1128/JCM.01309-12
PMCID: PMC3486215  PMID: 22875896
15.  Update on the success of the pneumococcal conjugate vaccine 
Paediatrics & Child Health  2011;16(4):233-236.
Several years after the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in Canada and elsewhere, routine infant vaccination has led to near eradication of invasive pneumococcal disease caused by vaccine serotype strains in both children and adults. There have also been significant declines in pneumococcal-related disease including lobar pneumonia and otitis media. These declines have been offset, to some extent, by increases in nonvaccine serotype disease. Serotype 19A, which is often highly resistant to antibiotics, has become predominant. In most populations, however, the magnitude of replacement disease is much lower than the magnitude of decline in invasive pneumococcal disease with the use of PCV7. There is increasing evidence that three PCV7 doses provide protection that is nearly identical to that of four doses. New 10-valent and 13-valent pneumococcal conjugate vaccines were recently approved in Canada. These vaccines increase pneumococcal serotype coverage including serotype 19A (present in the 13-valent vaccine). Many provinces and territories have incorporated the 13-valent vaccine in their vaccination programs.
PMCID: PMC3076178  PMID: 22468128
Conjugate vaccine; Infant; Meningitis; Pneumococcal disease; Streptococcus pneumoniae; Vaccination
16.  Streptococcus pneumoniae Serotype-2 Childhood Meningitis in Bangladesh: A Newly Recognized Pneumococcal Infection Threat 
PLoS ONE  2012;7(3):e32134.
Background
Streptococcus pneumoniae is a leading cause of meningitis in countries where pneumococcal conjugate vaccines (PCV) targeting commonly occurring serotypes are not routinely used. However, effectiveness of PCV would be jeopardized by emergence of invasive pneumococcal diseases (IPD) caused by serotypes which are not included in PCV. Systematic hospital based surveillance in Bangladesh was established and progressively improved to determine the pathogens causing childhood sepsis and meningitis. This also provided the foundation for determining the spectrum of serotypes causing IPD. This article reports an unprecedented upsurge of serotype 2, an uncommon pneumococcal serotype, without any known intervention.
Methods and Findings
Cases with suspected IPD had blood or cerebrospinal fluid (CSF) collected from the beginning of 2001 till 2009. Pneumococcal serotypes were determined by capsular swelling of isolates or PCR of culture-negative CSF specimens. Multicenter national surveillance, expanded from 2004, identified 45,437 patients with suspected bacteremia who were blood cultured and 10,618 suspected meningitis cases who had a lumber puncture. Pneumococcus accounted for 230 culture positive cases of meningitis in children <5 years. Serotype-2 was the leading cause of pneumococcal meningitis, accounting for 20.4% (45/221; 95% CI 15%–26%) of cases. Ninety eight percent (45/46) of these serotype-2 strains were isolated from meningitis cases, yielding the highest serotype-specific odds ratio for meningitis (29.6; 95% CI 3.4–256.3). The serotype-2 strains had three closely related pulsed field gel electrophoresis types.
Conclusions
S. pneumoniae serotype-2 was found to possess an unusually high potential for causing meningitis and was the leading serotype-specific cause of childhood meningitis in Bangladesh over the past decade. Persisting disease occurrence or progressive spread would represent a major potential infection threat since serotype-2 is not included in PCVs currently licensed or under development.
doi:10.1371/journal.pone.0032134
PMCID: PMC3316528  PMID: 22479314
17.  Effect of heptavalent pneumococcal conjugate vaccination on invasive pneumococcal disease in preterm born infants 
Background
Evidence for protection of preterm born infants from invasive pneumococcal disease (IPD) by 7-valent pneumococcal conjugate vaccination (PCV7) is relatively sparse. Data from randomized trials is based on relatively small numbers of preterm born children.
Methods
We report data from active prospective surveillance of IPD in children in Germany. The cohorts of preterm born children in 2000 and 2007 and the respective whole birth cohorts are compared regarding occurrence of IPD.
Results
After introduction of PCV7 we observed a reduction in the rate of IPD in preterm born infants comparing the 2000 and 2007 birth cohort. The rate of IPD among the whole birth cohorts was reduced from 15.0 to 8.5 notifications per 100,000 (P < .001). The impact among the preterm birth cohort was comparable: A reduction in notification rate from 26.1 to 16.7 per 100,000 comparing the 2000 with the 2007 preterm birth cohort (P = .39). Preterm born infants with IPD were either unvaccinated or vaccinated delayed or incomplete.
Conclusions
This adds to evidence that PCV7 also protects preterm born infants effectively from IPD. Preterm born infants should receive pneumococcal vaccination according to their chronological age.
doi:10.1186/1471-2334-10-12
PMCID: PMC2823613  PMID: 20085656
18.  Pediatric Invasive Pneumococcal Disease Caused by Vaccine Serotypes following the Introduction of Conjugate Vaccination in Denmark 
PLoS ONE  2013;8(1):e51460.
A seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the Danish childhood immunization program (2+1 schedule) in October 2007, followed by PCV13 starting from April 2010. The nationwide incidence of IPD among children younger than 5 years nearly halved after the introduction of PCV7 in the program, mainly due to a decline in IPD caused by PCV7-serotypes. We report the results from a nationwide population-based cohort study of laboratory confirmed IPD cases in children younger than 5 years during October 1, 2007 to December 31, 2010 and describe the characteristics of children suspected to present with a vaccine failure. The period between April 19 and December 31, 2010 was considered a PCV7/PCV13 transitional period, where both vaccines were offered. We identified 45 episodes of IPD caused by a PCV7 serotype (23% of the total number) and 105 (55%) caused by one of the 6 additional serotypes in PCV13. Ten children had received at least one PCV7 dose before the onset of IPD caused by a PCV7 serotype. Seven children were considered to be incompletely vaccinated before IPD, but only three cases fulfilled the criteria of vaccine failure (caused by serotypes 14, 19F and 23F). One case of vaccine failure was observed in a severely immunosuppressed child following three PCV7 doses, and two cases were observed in immunocompetent children following two infant doses before they were eligible for their booster. None of the IPD cases caused by the additional PCV13 serotypes had been vaccinated by PCV13 and there were therefore no PCV13-vaccine failures in the first 8-months after PCV13 introduction in Denmark.
doi:10.1371/journal.pone.0051460
PMCID: PMC3554759  PMID: 23365635
19.  Cost-effectiveness of new adult pneumococcal vaccination strategies in Italy 
Community-acquired pneumonia (CAP) and invasive pneumococcal disease (IPD) are very relevant pathologies among elderly people (≥ 65 y old), with a consequent high disease burden. Immunization with the 23-valent pneumococcal polysaccharide vaccine (PPV23) has been differently implemented in the Italian regions in the past years, reaching overall low coverage rates even in those with medical indications. In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) became available and recommended in the universal Italian infant immunization program. Since October 2012, indications for use of PCV13 were extended to subjects ≥ 50 y to prevent invasive pneumococcal diseases. The Italian decision makers should now revise regional indications for the prevention of pneumococcal diseases in the elderly. Pharmaco-economic analyses represent a useful tool to value the feasibility of new immunization programs and their sustainability. Therefore, an ad hoc population model was developed in order to value the clinical and economic impact of an adult pneumococcal vaccination program in Italy.
Particularly, different immunization scenarios were modeled: vaccination of 65 y-olds (1 cohort strategy), simultaneous vaccination of people aged 65 and 70 y (double cohort strategy) and, lastly, immunization of people aged 65, 70 and 75 y (triple cohort strategy), thus leading to the vaccination of 5, 10 and 15 cohorts during the 5 y of the program. In addition, the administration of a PPV23 dose one year after PCV13 was evaluated, in order to verify the economic impact of the supplemental serotype coverage in elderly people. The mathematical model valued the clinical impact of PCV13 vaccination on the number of bacteraemic pneumococcal pneumonia (BPP) and pneumococcal meningitis (PM) cases, and related hospitalizations and deaths. Although PCV13 is not yet formally indicated for the prevention of pneumococcal CAP by the European Medicine Agency (differently from FDA, whose indications include all pneumococcal diseases in subjects ≥ 50 y), the model calculated also the possible impact of vaccination on CAP cases (non-bacteraemic), considering the rate of this disease due to S. pneumoniae. The results of the analysis show that, in Italy, an age-based PCV13 vaccination program in elderly people is cost-effective from the payer perspective, with costs per QALY ranging from 17,000 to 22,000 Euro, according to the adopted vaccination strategy. The subsequent PPV23 offer results in an increment of costs per QALY (from 21,000 to 28,000 Euro, according to the vaccination strategy adopted). Pneumococcal vaccination using the conjugate vaccine turned out to be already favorable in the second year of implementation, with incremental costs per QALY comparable to those of other already adopted prevention activities in Italy (for instance, universal HPV vaccination of 12 y-old girls), with further benefits obtained when extending the study period beyond the 5-y horizon of our analysis.
doi:10.4161/hv.23268
PMCID: PMC3891731  PMID: 23295824
pneumococcal conjugate vaccine; elderly; economic evaluation; cost-effectiveness; pneumococcal disease
20.  Community-acquired pneumonia in children 
Paediatrics & Child Health  2003;8(10):616-619.
Community acquired pneumonia (CAP) is common in childhood. Viruses account for most cases of CAP during the first two years of life. After this period, bacteria such as Streptococcus pneumoniae, Mycoplasma pneumoniae and Chlamydia pneumoniae become more frequent. CAP symptoms are nonspecific in younger infants, but cough and tachypnea are usually present in older children. Chest x-ray is useful for confirming the diagnosis. Most children can be managed empirically with oral antibiotics as outpatients without specific laboratory investigations. Those with severe infections or with persistent or worsening symptoms need more intensive investigations and may need admission to hospital. The choice and dosage of antibiotics should be based on the age of the patient, severity of the pneumonia and knowledge of local antimicrobial resistance patterns. The Canadian Paediatric Society recommends the use of the heptavalent conjugate pneumococcal vaccine, which is efficacious in reducing chest x-ray positive pneumonia by up to 20%.
PMCID: PMC2795279  PMID: 20019854
Childhood; Community-acquired; Diagnosis; Pneumonia
21.  Epidemiology of Invasive Pneumococcal Disease in Older People in Spain (2007–2009): Implications for Future Vaccination Strategies 
PLoS ONE  2012;7(8):e43619.
Background
Recently, the 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended for adults. We analyzed the epidemiology of invasive pneumococcal disease (IPD) in older adults in Spain before PCV13 introduction.
Methodology/Principal Findings
IPD episodes, defined as clinical findings together with an invasive pneumococcal isolate, were prospectively collected from patients aged over 65 years in three hospitals in Spain from 2007 to 2009. A total of 335 IPD episodes were collected. Pneumonia was the main clinical syndrome, while chronic obstructive pulmonary disease, diabetes mellitus and cancer were the main underlying diseases. Pneumococcal isolates were serotyped and the molecular typing was performed by PFGE/MLST. PCV13 serotypes accounted for 59.3% of isolates, the most prevalent being serotypes 19A (15.1%), 3 (9.6%), 7F (7.5%), 14 (6.9%) and 1 (5.4%). The most frequent non-PCV13 serotypes were serotypes 16F (4.5%), 22F (3.6%), 24F (3.3%) and 6C (2.1%). The most common genotypes were CC230 (8.5%, serotypes 19A and 24F), CC156 (8.2%, serotypes 9V and 14), ST191 (7.9%, serotype 7F), CC260 (6.6%, serotype 3), ST306 (5.2%, serotype 1), CC30 (4.6%, serotype 16F) and ST433 (3.6%, serotype 22F). Comparing the 335 IPD isolates to 174 invasive pneumococci collected at the same hospitals in 1999–2000, PCV7 serotypes decreased (45.4% vs 18.4%,p<0.001), non-PCV7 serotypes included in PCV13 increased (26.4% vs 41.0%,p = 0.001) and two non-PCV13 serotypes increased (serotype 6C 0% vs 2.1%, p = 0.05; serotype 24F 0.6% vs 3.3%, p = 0.04,).
Conclusion
In our older adult population two serotypes (19A and 3) included in PCV13 accounted for about a quarter of IPD episodes in people ≥65 years. Non-PCV13 emerging serotypes should be carefully monitored in future surveillance studies.
doi:10.1371/journal.pone.0043619
PMCID: PMC3425535  PMID: 22928005
22.  Safety, immunogenicity and efficacy of pneumococcal conjugate vaccine in HIV-infected individuals 
Streptococcus pneumoniae is the leading bacterial opportunistic infection in HIV-infected individuals. Anti-retroviral treatment (ART) of HIV-infected individuals reduces their risk of invasive pneumococcal disease (IPD), however, it remains 20- to 40-fold greater compared with age-matched general population. This review summarizes the available published data on the immunogenicity, safety and efficacy of pneumococcal polysaccharide-protein conjugate vaccines (PCV) in HIV-infected children and adults.
 
Several studies have demonstrated that PCV are safe in the HIV-infected persons. Although PCV are immunogenic in HIV-infected infants, the antibodies produced are functionally impaired, there is possibly a lack or loss of anamnestic responses and immunity declines in later life However, quantitative and qualitative antibody responses to PCV in HIV-infected infants are enhanced when vaccination occurs whilst on ART, as well as if vaccination occurs when the CD4+ cell percentage is ≥ 25% and if the nadir CD4+ is >15%. Although the efficacy of PCV was lower, the vaccine preventable burden of hospitalization for IPD and clinical pneumonia were 18-fold and 9-fold greater, respectively, in HIV-infected children compared with –uninfected children.
In HIV-infected adults, PCV vaccination induces more durable and functional antibody responses in individuals on ART at the time of vaccination than in ART-naive adults, independently of baseline CD4+ cell count, although there does not appear to be much benefit from a second-dose of PCV. PCV has also been shown to reduce the risk of recurrent IPD by 74% in HIV-infected adults not on ART, albeit, also with subsequent decline in immunity and protection.
doi:10.4161/hv.18432
PMCID: PMC3367711  PMID: 22426374
Streptococcus pneumoniae; HIV; immunogenicity; pneumococcal conjugate vaccine; pneumococcal disease
23.  7-Valent Pneumococcal Conjugate Vaccination in England and Wales: Is It Still Beneficial Despite High Levels of Serotype Replacement? 
PLoS ONE  2011;6(10):e26190.
Background
The UK introduced the 7-valent pneumococcal conjugate vaccine (PCV7) into the national vaccination program in September 2006. Previous modelling assumed that the likely impact of PCV7 on invasive pneumococcal disease (IPD) would be similar to the US experience with PCV7. However, recent surveillance data show a more rapid replacement of PCV7 IPD cases by non-PCV7 IPD cases than was seen in the US.
Methods and Findings
A previous model of pneumococcal vaccination was re-parameterised using data on vaccine coverage and IPD from England and Wales between 2006 and 2009. Disease incidence was adjusted for the increasing trend in reported IPD cases prior to vaccination. Using this data we estimated that individuals carrying PCV7 serotypes have much higher protection (96%;95% CI 72%-100%) against acquisition of NVT carriage than the 15% previously estimated from US data, which leads to greater replacement. However, even with this level of replacement, the annual number of IPD cases may be 560 (95% CI, -100 to 1230) lower ten years after vaccine introduction compared to what it may have been without vaccination. A particularly marked fall of 39% in children under 15 years by 2015/6 is predicted.
Conclusion
Our model suggests that PCV7 vaccination could result in a decrease in overall invasive pneumococcal disease, particularly in children, even in an environment of rapid replacement with non-PCV7 serotypes within 5 years of vaccine introduction at high coverage.
doi:10.1371/journal.pone.0026190
PMCID: PMC3193519  PMID: 22022559
24.  Systematic Review of the Effect of Pneumococcal Conjugate Vaccine Dosing Schedules on Vaccine-type Invasive Pneumococcal Disease Among Young Children 
The Pediatric Infectious Disease Journal  2013;33(Suppl 2 Optimum Dosing of Pneumococcal Conjugate Vaccine For Infants 0 A Landscape Analysis of Evidence Supportin g Different Schedules):S109-S118.
Background:
Pneumococcal conjugate vaccines (PCV) are being implemented globally using a variety of different schedules. The optimal schedule to maximize protection of vaccinated children against vaccine-type invasive pneumococcal disease (VT-IPD) is not known.
Methods:
To assess the relative benefit of various PCV dosing schedules, we conducted a systematic review of studies published in English from 1994 to 2010 (supplemented post hoc with studies from 2011) on PCV effectiveness against VT-IPD among children targeted to receive vaccine. Data on 2-dose and 3-dose primary series, both with and without a booster (“2+0,” “2+1,” “3+0” and “3+1”), were included. For observational studies using surveillance data or case counts, we calculated percentage reduction in VT-IPD before and after PCV introduction.
Results:
Of 4 randomized controlled trials and 31 observational studies reporting VT-IPD among young children, none evaluated a 2+0 complete series, 7 (19%) evaluated 2+1, 4 (11%) 3+0 and 27 (75%) 3+1. Most (86%) studies were from North America or Europe. Only 1 study (observational) directly compared 2 schedules (3+0 vs. 3+1); results supported the use of a booster dose. In clinical trials, vaccine efficacy ranged from 65% to 71% with 3+0 and 83% to 94% with 3+1. Surveillance data and case counts demonstrate reductions in VT-IPD of up to 100% with 2+1 (6 studies) or 3+1 (17 studies) schedules and up to 90% with 3+0 (2 studies). Reductions were observed as early as 1 year after PCV introduction.
Conclusions:
These data support the use of 2+1, 3+0 and 3+1 schedules, although most data of PCV impact on VT-IPD among young children are from high-income countries using 3+1. Differences between schedules for impact on VT-IPD are difficult to discern based on available data.
doi:10.1097/INF.0000000000000078
PMCID: PMC3944481  PMID: 24336053
pneumococcal conjugate vaccine; immunization schedule; invasive disease; systematic review
25.  Effectiveness and cost-effectiveness of general immunisation of infants and young children with the heptavalent conjugated pneumococcal vaccine 
Background
The European Agency for the Evaluation of Medicinal Products (EMEA) granted market authorisation to the heptavalent pneumococcal vaccine Prevenar (Wyeth) in the year 2001. The indication of Prevenar is the active immunisation of infants and young children under the age of two against invasive disease caused by Streptococcus pneumonia serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. At the time of this study the German vaccination scheme advises the immunisation with Prevenar only for children at high risk.
Objectives
The objective of the study is first to determine the efficacy and effectiveness of the immunisation of all children with the heptavalent conjugated pneumococcal vaccine in Germany and second, whether a general recommendation for vaccination of all children would be cost-effective.
Methods
A systematic literature search was performed in 29 relevant databases for the period of January 1999 to June 2004. Thus 1,884 articles were identified which were then assessed according to predefined selection criteria.
Results
There is evidence for the medical effectiveness of Prevenar against invasive pneumococcal disease caused by the covered serotypes from a major double-blinded RCT undertaken in California. The vaccine shows lower values of effectiveness against otitis media and pneumonia. The values for effectiveness of the vaccine in Germany are below the data for California because of the different incidence of Serotypes. The cost-effectiveness rates for an immunisation of all children with Prevenar vary across different countries. One reason - besides different Health Systems - can be seen in the uncertainty about the duration of protection, another in the assumption on regional serotype coverage of the vaccine. From the healthcare payers' perspective a general vaccination of all children in Germany is not cost-effective, from a societal perspective the benefits from vaccination could prevail the cost. The actual price of the vaccine (if financed by the Healthcare Payer, 2004) has dropped and is lower than the assumed price in the German cost-effectiveness study. This fact could raise the cost-effectiveness-ratio of a general immunisation.
Discussion
The low evidence of information on the herd immunity effect of pneumococcal immunisation, the occurrence on serotype-replacement phenomenon and the effects on the prevalence of antibiotic-resistant strains shall be considered when deciding whether the pneumococcal vaccination for all infants and young children should be added to the German vaccination scheme. There is also little information on the duration of vaccine effectiveness and regional effectiveness because of different serotype incidence. The economic models thus incorporate some uncertainties.
Conclusion
At present, relatively few pneumococcal strains in Germany show antibiotic resistance. This situation shall further be observed while improving the data evidence for future decisions (epidemiologic data of incidence of pneumococcal diseases and serotyping of pneumococcal bacteria). From the economic perspective no distinct recommendation to add the conjugated vaccination for all children to the German vaccination scheme can be given. This situation may change if the price for the vaccine further decreases. Furthermore a future cost-effectiveness analysis for Germany should incorporate the effects of the replacement phenomenon, the herd immunisation effects and the effects of the vaccination on the antibiotic-resistant pneumococcal strains.
PMCID: PMC3011321  PMID: 21289926

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