The evidence for using conjugate vaccines to protect HIV-infected children against pneumococcal disease

Pneumococcal conjugate vaccines (PCVs) are a potentially useful complement to existing treatment strategies in HIV-infected children, for whom pneumococcal infections are common and serious. This Review summarises available data on the burden of pneumococcal disease and the safety and efficacy of PCVs in HIV-infected children. The data demonstrate that children with HIV have significantly increased risk of pneumococcal disease compared with uninfected children; the serotypes included in currently licensed or near-licensure conjugate vaccines include most serotypes that cause invasive pneumococcal disease (IPD) in HIV-infected children and adults; PCVs provide substantial protection against IPD and clinical pneumonia when given to HIV-infected infants; and HIV-infected adults gain an indirect benefit when children in the community are vaccinated. PCV should be considered as an important intervention for improving the lives of HIV-infected children.     

Prevention of pneumococcal diseases in the post-seven valent vaccine era: A European perspective

ABSTRACT: BACKGROUND: The burden of invasive pneumococcal disease in young children decreased dramatically following introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) The epidemiology of S. pneumoniae now reflects infections caused by serotypes not included in PCV7. Recently introduced higher valency pneumococcal vaccines target the residual burden of invasive and non-invasive infections, including those caused by serotypes not included in PCV7. This review is based on presentations made at the European Society of Pediatric Infectious Diseases in June 2011. DISCUSSION: Surveillance data show increased circulation of the non-PCV7 vaccine serotypes 1, 3, 6A, 6C, 7 F and 19A in countries with routine vaccination. Preliminary evidence suggests that broadened serotype coverage offered by higher valency vaccines may be having an effect on invasive disease caused by some of those serotypes, including 19A, 7 F and 6C. Aetiology of community acquired pneumonia remains a difficult clinical diagnosis. However, recent reports indicate pneumococcal vaccination has reduced hospitalisations of children for vaccine serotype pneumonia. Variations in serotype circulation and occurrence of complicated and non-complicated pneumonia caused by non-PCV7 serotypes highlight the potential of higher valency vaccines to decrease the remaining burden. PCVs reduce nasopharyngeal carriage and acute otitis media (AOM) caused by vaccine serotypes. Recent investigations of the interaction between S. pneumoniae and non-typeable H. influenzae suggest that considerable reduction in severe, complicated AOM infections may be achieved by prevention of early pneumococcal carriage and AOM infections. Extension of the vaccine serotype spectrum beyond PCV7 may provide additional benefit in preventing the evolution of AOM. The direct and indirect costs associated with pneumococcal disease are high, thus herd protection and infections caused by non-vaccine serotypes both have strong effects on the cost effectiveness of pneumococcal vaccination. Recent evaluations highlight the public health significance of indirect benefits, prevention of pneumonia and AOM and coverage of non-PCV7 serotypes by higher valency vaccines. SUMMARY: Routine vaccination has greatly reduced the burden of pneumococcal diseases in children. The pneumococcal serotypes present in the 7-valent vaccine have greatly diminished among disease isolates. The prevalence of some non-vaccine serotypes (e.g. 1, 7 F and 19A) has increased. Pneumococcal vaccines with broadened serotype coverage are likely to continue decreasing the burden of invasive disease, and community acquired pneumonia in children. Further reductions in pneumococcal carriage and increased prevention of early AOM infections may prevent the evolution of severe, complicated AOM. Evaluation of the public health benefits of pneumococcal conjugate vaccines should include consideration of non-invasive pneumococcal infections, indirect effects of vaccination and broadened serotype coverage.     

Incidence of pneumococcal infections among children under 15 years in southern Catalonia throughout the heptavalent conjugate vaccine era, 2002–2009

Purpose

Updating epidemiological studies to document current incidences of pneumococcal diseases are greatly needed in the current era of new pneumococcal conjugate vaccines (PCVs). The aim of this study is to analyze the incidence and distribution of different serotypes causing pneumococcal infections among the pediatric population in southern Catalonia, Spain, throughout the 2002–2009 PCV7 eras.

Methods

A population-based surveillance study was conducted among children aged ≤14 years in the region of Tarragona (Catalonia, Spain) during the period 2002–2009. All cases of pneumococcal infections (invasive and non-invasive cases) were included in the study. Incidence rates (per 100,000 population-year) and prevalence of infections caused by serotypes included in different PCV formulations were calculated for the 2002–2005 and 2006–2009 periods.

Results

Globally, across the total 2002–2009 period, the incidence of pneumococcal infections was 48.2 per 100,000 children-year (22.4 and 25.8 for invasive and non-invasive infections, respectively). Between 2002–2005 and 2006–2009, the incidence rates largely decreased among children aged <2 years (from 171 to 111 per 100,000 children-year; p = 0.059), but they did not substantially vary among children aged 2–14 years. The percentages of cases caused by serotypes included in PCV7 (60.0 vs. 16.7 %; p < 0.001), PCV10 (75.0 vs. 47.4 %; p = 0.028), and PCV13 (85.0 vs. 70.5 %; p = 0.190) decreased in both periods.

Conclusion

In this study, which was conducted in a setting with intermediate PCV7 uptakes, a considerable protective direct effect of vaccination occurred among young infants, but an indirect protective effect did not emerge in the rest of the pediatric population. Despite new PCVs with higher serotype coverage, an important proportion of pneumococcal infections is still not covered by these vaccines.     

Combined schedules of pneumococcal conjugate and polysaccharide vaccines: is hyporesponsiveness an issue?

Streptococcus pneumoniae is a major cause of morbidity and mortality in children less than 5 years of age. Prevention of pneumococcal disease and death in children in the developing world through vaccination with recently developed, highly efficacious pneumococcal conjugate vaccines (PCVs) is now possible. Schedules combining PCV with 23-valent pneumococcal polysaccharide vaccine (PPV23) have been studied and proposed as a means to expand disease protection against serotypes not included in the PCVs. Studies of group A and C meningococcal polysaccharide vaccine and repeated doses of PPV23 in adults and children have shown that a state of immune tolerance, or hyporesponsiveness, can develop to repeated polysaccharide vaccine antigen exposures. In this Review, we describe the evidence for and against this hyporesponsiveness and explore the possible mechanisms for such an occurrence.     

Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998-2004

BACKGROUND: Widespread use of pneumococcal conjugate vaccine (PCV7) resulted in decreases in invasive disease among children and elderly persons. The benefits may be offset by increases in disease due to serotypes not included in the vaccine (hereafter, "nonvaccine serotypes"). We evaluated the effect of PCV7 on incidence of disease due to nonvaccine serotypes. METHODS: Cases of invasive disease were identified in 8 geographic areas through the Centers for Disease Control and Prevention's Active Bacterial Core surveillance. Serotyping and susceptibility testing of isolates were performed. We calculated the incidence of disease for children aged <5 years and adults aged > or =65 years. We compared rates of serotype-specific disease before and after PCV7 was licensed for use. RESULTS: The annual incidence of disease due to nonvaccine serotypes increased from an average of 16.3 cases/100,000 population during prevaccine years (1998-1999) to 19.9 cases/100,000 population in 2004 for children aged <5 years (P=.01) and from 27.0 cases/100,000 population during prevaccine years to 29.8 cases/100,000 population in 2004 for adults aged > or =65 years (P=.05). Significant increases in the incidences of disease due to serotypes 3, 15, 19A, 22F, and 33F were observed among children during this period (P<.05 for each serotype); serotype 19A has become the predominant cause of invasive disease in children. The incidence of disease due to these serotypes also increased among elderly persons. CONCLUSIONS: The incidence of pneumococcal disease caused by nonvaccine serotypes is increasing. Ongoing surveillance is needed to monitor the magnitude of disease caused by nonvaccine serotypes, to ensure that future vaccines target the appropriate serotypes.     

Pneumococcal Vaccination in Adults: What Can We Learn From Observational Studies That Evaluated PCV13 and PPV23 Effectiveness in the Same Population?

IntroductionFifteen and 20-valent pneumococcal conjugate vaccines (PCV15; PCV20) were recently licensed to prevent pneumococcal disease in adults. In the absence of efficacy or effectiveness data for these new vaccines, studies comparing 23-valent pneumococcal polysaccharide vaccine (PPV23) and PCV13 might help inform decision-making on how to best implement expanded-valency PCVs. Comparing PPV23 and PCV13 is problematic, as no head-to-head clinical trials evaluated efficacy. Comparing effectiveness results across observational studies that vary by population, design, and outcomes is difficult. To address these limitations, we undertook a narrative review of studies that assessed PPV23 and PCV13 vaccine effectiveness (VE) in the same adult populations.MethodsWe conducted a literature search in PubMed and Google Scholar and screened 525 studies using a standardized evaluation framework.ResultsNine studies met inclusion criteria, all from high-income countries. None evaluated invasive pneumococcal disease (IPD) alone. VE against vaccine-type pneumococcal pneumonia ranged from 2 to 6% for PPV23 and 41 to 71% for PCV13. VE against pneumococcal pneumonia or severe pneumococcal disease (IPD or pneumococcal pneumonia) ranged from ?10 to 11% for PPV23, 40 to 79% for PCV13, and 39 to 83% for sequential PCV13/PPV23. VE against all-cause pneumonia or lower respiratory tract infection ranged from ?8 to 3% for PPV23 and 9 to 12% for PCV13.ConclusionsOverall, PCV13 demonstrated better protection than PPV23 against pneumococcal disease and all-cause respiratory outcomes in the included studies. Where evaluated, sequential PCV13/PPV23 vaccination showed little benefit over PCV13 alone. Results support the use of PCVs to protect against pneumococcal disease and respiratory infections in adults.     

Routine Pneumococcal Vaccination of Children Provokes New Patterns of Serotypes Causing Invasive Pneumococcal Disease in Adults and Children

IntroductionRoutine vaccination of infants with protein-conjugated 7-valent pneumococcal vaccine (PCV7) begun in 2000 initiated a sea change of prevalent serotypes (STs) in invasive pneumococcal disease (IPD). The authors investigated in 1 community all STs causing IPD during 5 years before (PRE) and 2, 5-year periods after (POST1 and POST2) its initiation and found that PCV7 adversely affected ST coverage of 23-valent pneumococcal polysaccharide vaccine (PPV23) among adults.MethodsFrom 1996–2010, 620 consecutive Streptococcus pneumoniae IPD strains from adults (521) and children (99) hospitalized with IPD in Huntington, WV, were collected. Each strain was typed by Quellung reaction. The Marshall University Institutional Review Board approved this study.ResultsBy 6 to 10 years after the initiation of PCV7, IPD in children decreased significantly, whereas IPD in adults increased significantly. In both adults and children, IPD due to PCV7 STs decreased significantly. In adults with IPD, PCV7 STs were replaced by several non-PCV7 STs including STs contained in PPV23 but not in PCV7 and STs not contained in either vaccine. IPD due to 4 nonsusceptible STs included in PCV7 decreased from PRE to POST1 and POST2. IPD due to nonsusceptible STs not included in PCV7 increased from PRE to POST1 and POST2.ConclusionsRoutine PCV7 decreased IPD in children but not in adults. Predominant STs changed—children exhibited fewer PCV7 STs and adults exhibited fewer PCV7 and PPV23 STs—reducing vaccine coverage and increasing the risk of replacement STs causing IPD in adults.     

Risk of invasive pneumococcal disease in children with sickle cell disease in the era of conjugate vaccines: a systematic review of the literature

Pneumococcal conjugate vaccines (PCVs) are highly effective in preventing invasive pneumococcal diseases (IPD) in children, including those with sickle cell disease (SCD). A systematic review of the English literature published between 2000 and 2017 was undertaken to evaluate the serotype distribution, clinical presentation and outcomes of IPD in children with SCD in PCV programmes. We identified 475 potential studies and included 16 publications, involving 9438 children up to 22 years of age with SCD and 182 IPD episodes (prevalence, 1·9%. 95% confidence interval [CI], 1·7–2·2%). Septicaemia was the most prevalent clinical presentation (84/137; 61%) followed by lower respiratory tract infection (39/137; 29%) and meningitis (12/137, 9%). More than half the serotypes associated with IPD (88/148; 59·5%) were not included in the 13-valent PCV; of these, 54% (44/82) were due to serogroup 15. The crude case fatality rate was 11·5% (21/182 cases; 95% CI, 7·3–17·1%). Most cases of IPD in children with SCD were due to serotypes that are not included in any of the licensed PCVs. IPD in children with SCD remains associated with high morbidity and mortality, highlighting the importance of strict adherence to daily penicillin prophylaxis. Until a serotype-independent pneumococcal vaccine becomes available, higher-valent PCVs should include serogroup 15 to protect this highly vulnerable group of children.     

Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study

Background

The seven-valent pneumococcal conjugate vaccine (PCV7) has reduced vaccine-type (VT) invasive pneumococcal disease but increases in non-vaccine-type (NVT) disease have varied between countries. We assess the effect of the PCV7 vaccination on VT and NVT disease in England and Wales.

Methods

The study cohort was the population of England and Wales from July, 2000, to June, 2010. We calculated incidence rate ratios (IRRs) to compare incidences of VT and NVT disease before (2000–06) and after (2009–10) the introduction of PCV7. We used data from the national surveillance database. Cases included in our analysis were restricted to those confirmed by culture linked with isolates referred for serotyping at the national reference centre by laboratories in England and Wales. We adjusted for potential bias from missing data (serotype and age of patient) and changes in case ascertainment rates during the study period.

Findings

5809 cases of invasive pneumococcal disease were reported in 2009–10, giving an incidence of 10·6 per 100?000 population in 2009–10, which, when compared with the adjusted average annual incidence of 16·1 in 2000–06, gives an overall reduction of 34% (95% CI 28–39). VT disease decreased in all age groups, with reductions of 98% in individuals younger than 2 years and 81% in those aged 65 years or older. NVT disease increased by 68% in individuals younger than 2 years and 48% in those aged 65 years or older, giving an overall reduction in invasive pneumococcal disease of 56% in those younger than 2 years and 19% in those aged 65 years or older. After vaccine introduction, more NVT serotypes increased in frequency than decreased, which is consistent with vaccine-induced replacement. Key serotypes showing replacement were 7F, 19A, and 22F. Increases in NVT invasive pneumococcal disease were not associated with antimicrobial resistance.

Interpretation

Despite much serotype replacement, a substantial reduction in invasive pneumococcal disease in young children can be achieved with PCV7 vaccination, with some indirect benefit in older age groups. Further reductions should be achievable by use of higher valency vaccines. Robust surveillance data are needed to properly assess the epidemiological effect of multivalent pneumococcal disease vaccines.

Funding

Health Protection Agency.     

Prevention of Invasive Pneumococcal Disease: Problems Emerged After Some Years of the 13-Valent Pneumococcal Conjugate Vaccine Use

Starting from 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in several countries. This paper discusses some of the problems recently emerged after PCV13 use and their clinical impact. The impact of PCV13 has been relevant and has saved millions of children and adults by severe infectious diseases. However, it seems likely that in the future, effectiveness of the vaccine might be even higher than that presently evidenced. This is because long-term administration of PCV13 to the pediatric population can favor a more extensive reduction of nasopharyngeal colonization with vaccine serotypes of both vaccinated and unvaccinated subjects and further reduce invasive pneumococcal disease in all the individuals (herd immunity). While waiting for new vaccines to be able to overcome the problem of a limited number of pneumococcal strains included in PCV13, it is recommended to increase pneumococcal vaccination coverage in the entire pediatric population.     

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

ObjectivesThe overall reported burden of invasive pneumococcal disease (IPD) varies among countries in Europe. This review describes the epidemiology and serotype distribution of IPD in European children from studies published from 1990 to 2008.MethodsAverages were derived from all studies from all countries that had available data.ResultsBefore widespread immunization with 7-valent pneumococcal conjugate vaccine (PCV7), the overall mean annual incidence of IPD in children aged <2 years was 44.4/100 000. The mean case fatality rate for IPD was 3.5%, and resistant rates were approximately 23% for penicillin G (minimum inhibitory concentration ≥2 mg/l), 41% for erythromycin, and 9% (≤5 years) for third-generation cephalosporins. The most common serotypes causing IPD were 14, 6B, 19F, and 23F, all of which are included in PCV7. Vaccine serotype coverage ranged from 37% to 100% for PCV7, with mean increases in coverage of 7% and 16% for investigational 10- and 13-valent pneumococcal conjugate vaccines, respectively. The most common IPD isolates since PCV7 introduction in Belgium, France, Germany, Greece, Norway, Portugal, Spain, and the UK were serotypes 1, 19A, 3, 6A, and 7F.ConclusionsWith routine effective use of PCV7, a general decline in IPD, antibiotic non-susceptibility, and vaccine serotypes has been observed. The most common IPD isolates since PCV7 introduction are serotypes 1, 19A, 3, 6A, and 7F, highlighting the need for inclusion of these serotypes in future vaccine formulations.     

Serum serotype-specific pneumococcal anticapsular immunoglobulin g concentrations after immunization with a 9-valent conjugate pneumococcal vaccine correlate with nasopharyngeal acquisition of pneumococcus

BACKGROUND: Immunization with pneumococcal conjugate vaccines (PCVs) reduces nasopharyngeal colonization by Streptococcus pneumoniae. We attempted to correlate postvaccination serum serotype-specific pneumococcal anticapsular immunoglobulin (Ig) G concentrations with new acquisitions of vaccine-type (VT) serotypes and the VT-related serotype 6A. METHODS: A total of 132 day care center attendees aged 12-35 months received a 9-valent PCV (PnCRM9) and were followed for 2 years for new nasopharyngeal acquisitions of S. pneumoniae. A total of 132 control subjects received a meningococcus type C conjugate vaccine. Serum serotype-specific pneumococcal anticapsular IgG concentrations were determined at 1 month after complete immunization. RESULTS: A logistic regression model of the probability of having a new acquisition of S. pneumoniae (for serotypes 9V, 14, 19F, and 23F) as a function of the IgG concentration showed a negative coefficient, indicating that higher IgG concentrations led to a decreasing probability of having a new acquisition, and achieved statistical significance for serotypes 14 and 19F. Similarly, a new acquisition of serotype 6A was shown to be significantly inversely related to the anti-6B IgG concentration. An effect of the IgG concentration on duration of carriage was not demonstrated. CONCLUSION: The magnitude of herd protection against S. pneumoniae provided by a PCV may depend on the magnitude of IgG concentrations.     

Randomized,double-blind,controlled trial of pneumococcal vaccination in renal transplant recipients

Renal transplant recipients are at increased risk for developing invasive pneumococcal disease but may have a poor response to pneumococcal polysaccharide vaccine (PPV23). For them, pneumococcal conjugate vaccine (PCV7) may be more immunogenic. Patients were given a single dose of PPV23 or PCV7 in our randomized, controlled, double-blind trial. Immunogenicity was assessed 8 weeks after vaccination by serotype-specific enzyme-linked immunosorbent assay (ELISA) and opsonophagocytic assay (OPA). Baseline demographics, renal function, time since transplantation, and immunosuppression were comparable. In the PCV7 group, the vaccine response rate was improved for serotypes 23F (P=.046) and 6B (P=.067), and mean fold increases in antibody titer were higher for serotypes 23F (P=.046) and 9V (P=.09). The response rate and mean fold increase in OPA titers were not significantly different between groups. There was a trend toward enhanced immunogenicity for PCV7 by ELISA. However, functional antibody responses were not different.     

Indirect effect of conjugate vaccine on adult carriage of Streptococcus pneumoniae: an explanation of trends in invasive pneumococcal disease

BACKGROUND: Use of heptavalent protein-polysaccharide pneumococcal conjugate vaccine (PCV7) has been associated with decreases in PCV7-type invasive pneumococcal disease and nasopharyngeal (NP) carriage in children. Vaccine use has also indirectly decreased the rate of invasive disease in adults, presumably through decreased transmission of pneumococci from vaccinated children to adults. METHODS: We conducted NP carriage surveys in 8 villages in Alaska in 1998-2004. Streptococcus pneumoniae isolates were characterized by serotype and antimicrobial susceptibility. We analyzed trends in serotype distribution, antibiotic resistance, and factors associated with adult carriage of PCV7-serotype pneumococci before and after the introduction of PCV7 in 2001. RESULTS: We collected 15,598 NP swabs; overall, 52% of adults living in the villages surveyed participated in the colonization study. The proportion of adult carriers with PCV7-type pneumococcal carriage decreased from 28% of carriers in 1998-2000 to 4.5% of carriers in 2004 (P<.0001). Among adults, the proportion of colonizing isolates that were resistant to penicillin decreased from 13% in 1998-2000 to 6% in 2004 (P=.05), whereas the percentage of isolates with intermediate susceptibility to penicillin increased from 12% in 1998-2000 to 19% in 2004 (P<.01). Adults were more likely to carry PCV7-type pneumococci if they lived with a child <5 years old or if they lived with a child who had not been age-appropriately vaccinated with PCV7. CONCLUSIONS: Pediatric vaccination with PCV7 has resulted in decreased PCV7-type pneumococcal carriage among adults and helps to explain recent decreases in the rate of PCV7-type invasive pneumococcal disease among adults.     

Membrane particles evoke a serotype-independent cross-protection against pneumococcal infection that is dependent on the conserved lipoproteins MalX and PrsA

Pneumococcal conjugate vaccines (PCVs) used in childhood vaccination programs have resulted in replacement of vaccine-type with nonvaccine-type pneumococci in carriage and invasive pneumococcal disease (IPD). A vaccine based on highly conserved and protective pneumococcal antigens is urgently needed. Here, we performed intranasal immunization of mice with pneumococcal membrane particles (MPs) to mimic natural nasopharyngeal immunization. MP immunization gave excellent serotype-independent protection against IPD that was antibody dependent but independent of the cytotoxin pneumolysin. Using Western blotting, immunoprecipitation, mass spectrometry, and different bacterial mutants, we identified the conserved lipoproteins MalX and PrsA as the main antigens responsible for cross-protection. Additionally, we found that omitting the variable surface protein and vaccine candidate PspA from MPs enhanced protective immune responses to the conserved proteins. Our findings suggest that MPs containing MalX and PrsA could serve as a platform for pneumococcal vaccine development targeting the elderly and immunocompromised.

The pneumococcus (Streptococcus pneumoniae) is a major cause of morbidity and mortality globally, being the most common cause of respiratory tract infections such as otitis and sinusitis, but also a major contributor to more severe diseases such as pneumonia without or with sepsis and meningitis (i.e., invasive pneumococcal disease [IPD]) (1, 2). Risk groups for acquiring pneumococcal infections include young children, the elderly, immunocompromised individuals, and those with a prior influenza A virus infection. Current pneumococcal vaccines target a limited number of the 100 pneumococcal capsular serotypes identified so far (3–5). First, polysaccharide-based vaccines were launched (PPV23), but due to limited protection in the risk groups, so-called pneumococcal conjugate vaccines (PCVs) were introduced where the sugars are conjugated to a protein carrier to provide a stronger antibody response. Since 2010, 10-valent (PCV10) and 13-valent (PCV13) vaccines are used worldwide in childhood vaccination programs. PCV introduction has led to a significant decrease in IPD in vaccinated children and a reduction in nasopharyngeal carriage of vaccine type (VT) strains in healthy children (6–11). However, pneumococcal carriage rates in children have remained the same due to replacement of VT with nonvaccine type (NVT) strains (8, 9). This also resulted in an expansion of NVTs among IPD cases in nonvaccinated age groups, affecting the efficacy of the PCVs (12). Thus, in 2016 the IPD incidence among the elderly in Sweden did not decrease after PCV introduction, and more than 70% of cases were caused by NVTs (12). PCV13 includes an additional three serotypes not included in PCV10 (i.e., serotypes 3, 6A, and 19A). So far, its efficacy against IPD caused by serotype 3 is being debated (13), and in Sweden, serotype 3 now constitutes a major serotype among IPD cases in the elderly (8, 12). This underlines the importance of finding a new vaccine against serotype 3. Recently, a 20-valent vaccine was approved by the US Food and Drug Administration for adults, including PCV13 serotypes as well as serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F. Other vaccine approaches include protein-based vaccines. Recently, a study was published in which five pneumococcal candidates were identified and validated as immunogens. Zangari et al. (14) found protection against pneumococcal colonization using a nonencapsulated strain, but not against the encapsulated variant, suggesting that the capsule might affect mucosal protection.Like other gram-positive bacteria, pneumococci release extracellular vesicles (EVs) derived from their cytoplasmic membrane (15, 16). It has been suggested that colonization events during childhood generate serum antibodies to pneumococcal antigens (17). Several of these antigens relate to proteins that recently were shown to be enriched in purified EVs from liquid-grown bacteria (18, 19). We argue that EVs produced during colonization represent major vehicles for immunogens that may generate protective immunity toward carriage and IPD. Furthermore, we previously showed that pneumococcal EVs can be internalized by host cells such as respiratory epithelial and dendritic cells (DCs) and can lead to DC activation and release of proinflammatory cytokines (18). Also, in vivo experiments have shown that intramuscular immunization of mice with pneumococcal EVs protect mice after homologous serotype challenge (20).Here, we show that spontaneously produced pneumococcal membrane particles (MPs) isolated from plate-grown bacteria provide a serotype-independent cross-protection against IPD in mice that is antibody dependent but is not dependent on the pneumococcal cytotoxin pneumolysin (Ply). We identify the major protective antigens for cross-protection as the two conserved membrane-bound lipoproteins MalX and PrsA, which are both needed for full protection. We also suggest that the highly variable immunodominant surface protein PspA, which differs between pneumococcal serotypes, may mask immune responses to conserved membrane-bound proteins that could be used as antigens in vaccines.     

Distance to health services affects local-level vaccine efficacy for pneumococcal conjugate vaccine (PCV) among rural Filipino children

Pneumococcal conjugate vaccines (PCVs) have demonstrated efficacy against childhood pneumococcal disease in several regions globally. We demonstrate how spatial epidemiological analysis of a PCV trial can assist in developing vaccination strategies that target specific geographic subpopulations at greater risk for pneumococcal pneumonia. We conducted a secondary analysis of a randomized, placebo-controlled, double-blind vaccine trial that examined the efficacy of an 11-valent PCV among children less than 2 y of age in Bohol, Philippines. Trial data were linked to the residential location of each participant using a geographic information system. We use spatial interpolation methods to create smoothed surface maps of vaccination rates and local-level vaccine efficacy across the study area. We then measure the relationship between distance to the main study hospital and local-level vaccine efficacy, controlling for ecological factors, using spatial autoregressive models with spatial autoregressive disturbances. We find a significant amount of spatial variation in vaccination rates across the study area. For the primary study endpoint vaccine efficacy increased with distance from the main study hospital from −14% for children living less than 1.5 km from Bohol Regional Hospital (BRH) to 55% for children living greater than 8.5 km from BRH. Spatial regression models indicated that after adjustment for ecological factors, distance to the main study hospital was positively related to vaccine efficacy, increasing at a rate of 4.5% per kilometer distance. Because areas with poor access to care have significantly higher VE, targeted vaccination of children in these areas might allow for a more effective implementation of global programs.Of the estimated 7.6 million children under 5 who died in 2010, ∼1.39 million (18.3%) died from acute lower respiratory infections (ALRI) (1). Although ALRI mortality has decreased over the past decade, it remains the largest single cause of childhood mortality worldwide, particularly in less-developed countries in Africa, Southeast Asia, and the eastern Mediterranean (1–3). ALRI is caused by a variety of pathogens including Streptococcus pneumoniae, Haemophilus influenzae type b, respiratory syncytial virus and influenza virus (4). There are conflicting estimates in the scientific literature of the role each of these pathogens play in the overall burden of disease (1, 5, 6). O’Brien et al. suggest that S. pneumoniae is the leading cause of pneumonia, accounting for 826,000 (or 8%) of all deaths among children under 5 in 2000 (6). However, more recent estimates from the global burden of disease study (GBD) suggest a much smaller role for pneumococcus, accounting for only 168,000 ALRI deaths in children under 5 y in 2010 (2). Although the reporting years differ, and ALRI mortality has decreased over time, these significantly different estimates have sparked a debate about the proportion of ALRI mortality attributable to pneumococcus.Pneumococcal conjugate vaccines (PCVs) have been shown to be effective against invasive pneumococcal disease across a diverse set of populations. A PCV9 vaccine showed an efficacy of 17% in South Africa (7) and 37% in the Gambia (8) against radiologically confirmed pneumonia; a PCV11 vaccine showed an efficacy of 23% in the Philippines (9); and a PCV10 showed an efficacy of 22% in Latin America (10). Drawing from these large vaccine trials, the World Health Organization (WHO) now recommends that PCVs be included in childhood immunization programs worldwide. Special emphasis is placed on countries with high childhood mortality (under 5 mortality rate of >50 deaths/1,000 births) where “high and equitable coverage” is advocated to maximize the impact of pneumococcal vaccines (11).Although PCVs have been widely used in United States, and more recently in Europe, they have generally not been widely adopted in other regions largely due to the high cost of integrating PCVs into national programs (12). The cost of implementing a universal PCV vaccination strategy, along with the recent findings from GBD 2010, suggests a need to reconsider the recommendations for universal PCV coverage shifting to a focus on vaccination strategies that target specific geographic subpopulations at greater risk for pneumococcal pneumonia. However, targeted interventions require a detailed analysis of the efficacy of the PCV vaccine that takes sociodemographic and geographic factors into account. Subpopulations with higher rates of vaccine-preventable disease could be targeted for vaccination, providing large cost savings to national health programs over universal vaccination approaches. These savings would only be realized if the costs associated with delivering a vaccine to disparate subpopulations is the same or lower than the average cost nationally and if the benefits of the vaccine (both direct and indirect) are the same or higher than the average benefits nationally. In this study, we use spatial epidemiological methods to examine the spatial variation in vaccine efficacy (VE) and model ecological factors that drive spatial patterns to suggest how targeted vaccine strategies can be developed.     

Streptococcus pneumoniae serotype 19A in Latin America and the Caribbean: a systematic review and meta-analysis, 1990-2010

ABSTRACT: BACKGROUND: Pneumococcal conjugate vaccines (PCVs) are in the process of implementation in Latin America. Experience in developed countries has shown that they reduce the incidence of invasive and non-invasive disease. However, there is evidence that the introduction of PCVs in universal mass vaccination programs, combined with inappropriate and extensive use of antibiotics, could be associated to changes in non-PCV serotypes, including serotype 19A. We conducted a systematic review to determine the distribution of serotype 19A, burden of pneumococcal disease and antibiotic resistance in the region. METHODS: We performed a systematic review of serotype 19A data from observational and randomized clinical studies in the region, conducted between 1990 and 2010, for children under 6 years. Pooled prevalence estimates from surveillance activities with confidence intervals were calculated. RESULTS: We included 100 studies in 22 countries and extracted data from 63. These data reported 19733 serotyped invasive pneumococcal isolates, 3.8% of which were serotype 19A. Serotype 19A isolates were responsible for 2.4% acute otitis media episodes, and accounted for 4.1% and 4.4% of 4,380 nasopharyngeal isolates from healthy children and in hospitalbased/ sick children, respectively. This serotype was stable over the twenty years of surveillance in the region. A total of 53.7% Spn19A isolates from meningitis cases and only 14% from non meningitis were resistant to penicillin. CONCLUSIONS: Before widespread PCV implementation in this region, serotype 19A was responsible for a relatively small number of pneumococcal disease cases. With increased use of PCVs and a greater number of serotypes included, monitoring S. pneumoniae serotype distribution will be essential for understanding the epidemiology of pneumococcal disease.     

Serotype replacement in disease after pneumococcal vaccination

Vaccination with heptavalent pneumococcal conjugate vaccine (PCV7) has significantly reduced the burden of pneumococcal disease and has had an important public health benefit. Because this vaccine targets only seven of the more than 92 pneumococcal serotypes, concerns have been raised that non-vaccine serotypes (NVTs) could increase in prevalence and reduce the benefits of vaccination. Indeed, among asymptomatic carriers, the prevalence of NVTs has increased substantially, and consequently, there has been little or no net change in the bacterial carriage prevalence. In many populations, pneumococcal disease caused by NVT has increased, but in most cases this increase has been less than the increase in NVT carriage. We review the evidence for serotype replacement in carriage and disease, and address the surveillance biases that might affect these findings. We then discuss possible reasons for the discrepancy between near-complete replacement in carriage and partial replacement for disease, including differences in invasiveness between vaccine serotypes. We contend that the magnitude of serotype replacement in disease can be attributed, in part, to a combination of lower invasiveness of the replacing serotypes, biases in the pre-vaccine carriage data (unmasking), and biases in the disease surveillance systems that could underestimate the true amount of replacement. We conclude by discussing the future potential for serotype replacement in disease and the need for continuing surveillance.     

Chronic medical conditions associated with invasive pneumococcal diseases in inpatients in teaching hospitals in São Paulo city: Estimating antimicrobial susceptibility and serotype-coverage of pneumococcal vaccines

BackgroundChronic conditions increase the risk of invasive pneumococcal diseases (IPD). Pneumococcal vaccination remarkably reduced IPD morbimortality in vulnerable populations. In Brazil, pneumococcal vaccines are included in the National Immunization Program (PNI): PCV10 for < 2 years-old, and PPV23 for high risk-patients aged ≥ 2 years and institutionalized ≥ 60 years. PCV13 is available in private clinics and recommended in the PNI for individuals with certain underlying conditions.MethodsA retrospective study was performed using clinical data from all inpatients from five hospitals with IPD from 2016 to 2018 and the corresponding data on serotype and antimicrobial-non-susceptibility of pneumococcus. Vaccine-serotype-coverage was estimated. Patients were classified according to presence of comorbidities: healthy, without comorbidities; at-risk, included immunocompetent persons with specific medical conditions; high-risk, with immunocompromising conditions and othersResults406 IPD cases were evaluated. Among 324 cases with information on medical conditions, children < 5 years were mostly healthy (55.9%), while presence of comorbidity prevailed in adults ≥ 18 years old (> 82.0%). Presence of ≥1 risk condition was reported in ≥ 34.8% of adults. High-risk conditions were more frequent than at-risk in all age groups. Among high-risk comorbidity (n = 211), cancer (28%), HIV/AIDS (25.7%) and hematological diseases (24.5%) were the most frequent. Among at-risk conditions (n = 89), asthma (16.5%) and diabetes (8.1%) were the most frequent. Among 404 isolates, 42.9% belonged to five serotypes: 19A (14.1%), 3 (8.7%), 6C (7.7%), 4 and 8 (6.2% each); 19A and 6C expressed antimicrobial-non-susceptibility. The vaccine-serotype-coverage was: PCV10, 19.1%, PCV13, 43.8%; PCV15, 47.8%; PCV20, 62.9%; PCV21, 65.8%, and PPV23, 67.3%. Information on hospital outcome was available for 283 patients, of which 28.6% died. Mortality was 54.2% for those with meningitis.ConclusionVaccine with expanded valence of serotypes is necessary to offer broad prevention to IPD. The present data contribute to pneumococcal vaccination public health policies for vulnerable patients, mainly those with comorbidity and the elderly.     

Cost-effectiveness of 2 + 1 dosing of 13-valent and 10-valent pneumococcal conjugate vaccines in Canada

ABSTRACT: 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 (44,504 when considering both direct and indirect effects and 6,629 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.