Strain characteristics of Streptococcus pneumoniae carriage and invasive disease isolates during a cluster-randomized clinical trial of the 7-valent pneumococcal conjugate vaccine

Widespread use of 7-valent pneumococcal conjugate vaccine (PCV7) has led to significant reductions in disease while changing pneumococcal population dynamics via herd immunity and serotype replacement. We performed multilocus sequence typing (MLST) on 590 pneumococcal isolates obtained during the American Indian clinical trial of PCV7, in which communities were randomized for eligible children to receive either PCV7 or a meningococcal conjugate vaccine (MCV). Sequence types (STs) were analyzed to determine the impact of the vaccine on pneumococcal population structure and to assess the possible impact of pneumococcal genetic background on vaccine effects. One hundred forty-three STs were obtained, the most frequent being ST199, the only one that included vaccine serotypes (VTs), non-vaccine-associated nonvaccine serotypes (NVA/NVTs), and vaccine-associated serotypes (VATs). Serotype replacement observed in the PCV communities was due to a diverse population of STs, most of which also existed in the MCV communities. Possible capsular switching to create novel ST associations with NVA/NVTs was detected only once. Reductions in VTs and changes in VATs in PCV communities did not show evidence of variation by ST, after accounting for lower vaccine effectiveness against serotype 19F. These observations suggest the hypothesis that the vaccine acts as a "serotype filter": its effect on a particular strain can be predicted on the basis of the serotype of the strain, with little effect of genetic background (as assessed by MLST) over and above capsule. If sustained, such patterns provide some cause for optimism that rapid evolution of PCV escape strains with drug resistance or high virulence is unlikely.     

Streptococcus pneumoniae meningitis in Alberta pre- and postintroduction of the 7-valent pneumococcal conjugate vaccine

OBJECTIVE:

To describe the epidemiology, clinical characteristics, microbiology and outcomes of patients of all ages with Streptococcus pneumoniae meningitis two years pre- and postintroduction of a S pneumoniae 7-valent conjugate vaccine program in Alberta in children <2 years of age.

METHODS:

Between 2000 and 2004, all cases of invasive pneumococcal disease in Alberta were identified. From this cohort, patients with S pneumoniae meningitis were identified by chart review. Clinical data, laboratory data and in-hospital outcomes were collected.

RESULTS:

Of the 1768 cases of invasive pneumococcal disease identified between 2000 and 2004, 110 (6.2%) had S pneumoniae meningitis. The overall incidence was 0.7 per 100,000 persons and remained unchanged over the study period. The rate in children <2 years of age appeared to fall over time, from 10.5 per 100,000 persons in 2000 to five per 100,000 persons in 2004, although there was insufficient evidence of a statistically significant time trend within any age group. Overall, the mean age was 30 years and 47% were male. In-hospital mortality was 20%, ranging from 6% in those ≤2 years of age to 31% for those ≥18 years of age, despite appropriate antimicrobial therapy.

CONCLUSION:

The high mortality rate associated with S pneumoniae meningitis suggests that prevention by vaccination is critical. In children <2 years of age, there was a downward trend in the rate of S pneumoniae meningitis after implementation of the S pneumoniae 7-valent conjugate vaccine program, but rates were still high.     

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.     

Emerging pneumococcal carriage serotypes in a high-risk population receiving universal 7-valent pneumococcal conjugate vaccine and 23-valent polysaccharide vaccine since 2001

Background  

In Australia in June 2001, a unique pneumococcal vaccine schedule commenced for Indigenous infants; seven-valent pneumococcal conjugate vaccine (7PCV) given at 2, 4, and 6 months of age and 23-valent pneumococcal polysaccharide vaccine (23PPV) at 18 months of age. This study presents carriage serotypes following this schedule.     

Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine.

The safety, immunogenicity, and impact on carriage of a nonvalent pneumococcal vaccine given at ages 6, 10, and 14 weeks were examined in a double-blind, randomized, placebo-controlled trial in 500 infants in Soweto, South Africa. No serious local or systemic side effects were recorded. Significant antibody responses to all pneumococcal serotypes were observed 4 weeks after the third dose. Haemophilus influenzae type b polyribosylribitol phosphate (geometric mean titer, 11.62 microg/mL) and diphtheria (1.39 IU/mL) antibodies were significantly higher in children receiving pneumococcal conjugate, compared with placebo recipients (4.58 microgram/mL and 0.98 IU/mL, respectively). Nasopharyngeal carriage of vaccine serotypes decreased in vaccinees at age 9 months (18% vs. 36%), whereas carriage of nonvaccine serotypes increased (36% vs. 25%). Carriage of penicillin-resistant pneumococci (21% vs. 41%) and cotrimoxazole-resistant pneumococci (23% vs. 35%) were significantly reduced 9 months after vaccination, compared with controls.     

Epidemiology of acute otitis media caused by Streptococcus pneumoniae before and after licensure of the 7-valent pneumococcal protein conjugate vaccine

We studied, by pulsed-field gel electrophoresis, multilocus sequence typing and penicillin-binding protein 2b amplicon-restriction profiles, pneumococcal isolates recovered from children with acute otitis media during 1 January-31 December 1999 and 2001. The proportion of nonvaccine serogroups increased from 14.8% (13/88) to 36.5% (23/63) from 1999 to 2001 (P<.01). Among children who received at least 2 doses of the pneumococcal 7-valent protein conjugate (PNC7) vaccine, 46.7% (7/15) of the isolates had nonvaccine serogroups, compared with 20.8% (26/125) of the isolates from children who did not receive the PNC7 vaccine (P=.05). Overall, the serogroups involved in capsular switching were 6-19-NT, 6-14-35, 15-19, and the 19-Spanish 23F clone. In 1999 and 2001, 30.8% (4/13) and 26.1% (6/23) of the nonvaccine serogroups were implicated in capsular switching, respectively. Continued surveillance will be of great importance as the distribution of the PNC7 vaccine increases.     

Effect of age and vaccination with a pneumococcal conjugate vaccine on the density of pneumococcal nasopharyngeal carriage

Background.?This study evaluated the impact of age and pneumococcal vaccination on the density of pneumococcal nasopharyngeal carriage. Methods.?A cluster-randomized trial was conducted in rural Gambia. In 11 villages (the vaccine group), all residents received 7-valent pneumococcal conjugate vaccine (PCV-7), while in another 10 villages (the control group), only children <30 months old or born during the study period received PCV-7. Cross-sectional surveys (CSSs) were conducted to collect nasopharyngeal swabs before vaccination (baseline CSS) and 4, 12, and 22 months after vaccination. Pneumococcal density was defined using a semiquantitative classification (range, 1-4) among colonized individuals. An age-trend analysis of density was conducted using data from the baseline CSS. Mean pneumococcal density was compared in CSSs conducted before and after vaccination. Results.?Mean bacterial density among colonized individuals in the baseline CSS was 2.57 for vaccine-type (VT) and non-vaccine-type (NVT) pneumococci; it decreased with age (P?相似文献   

Impact of a conjugate vaccine on community-wide carriage of nonsusceptible Streptococcus pneumoniae in Alaska

BACKGROUND: Streptococcus pneumoniae is a leading cause of invasive bacterial disease and pneumonia among children. Antimicrobial resistance among pneumococci has increased in recent years and complicates treatment. The introduction of heptavalent pneumococcal conjugate vaccine (PCV7) could reduce acquisition of antimicrobial-resistant pneumococci. METHODS: We obtained 1350 nasopharyngeal swabs for culture from 1275 children aged 3-59 months presenting at 3 clinics in Anchorage, Alaska, during the winters of 2000, 2001, and 2002, as PCV7 was being introduced into the routine immunization schedule. We recorded the frequency of use of antibiotics as well as the dates of doses of PCV7 for enrolled children. We used multivariate logistic regression modeling to identify independent risk factors for overall carriage of pneumococci and carriage of PCV7-type pneumococci, cotrimoxazole-nonsusceptible (COT-NS) pneumococci, or penicillin-nonsusceptible (PCN-NS) pneumococci. RESULTS: The proportion of children who were up-to-date for age, with respect to PCV7 vaccination, increased from 0% in 2000 to 55% in 2002. Carriage of PCV7-type pneumococci decreased by 43% (P<.0001). Risk of carriage of PCV7-type pneumococci was lower in 2002 than in 2000, independent of vaccination status, suggesting an indirect effect of vaccination. Carriage of COT-NS, but not PCN-NS, pneumococci also decreased (38%; P=.02), not only among vaccinated children but also among unvaccinated children without recent use of antibiotics. CONCLUSIONS: Introduction of PCV7 into the routine infant immunization schedule in a community with a high prevalence of antimicrobial-resistant pneumococci appears to reduce transmission of PCV7 vaccine serotypes and COT-NS pneumococci but has no impact on overall carriage of pneumococci or carriage of PCN-NS pneumococci.     

Evaluation of Streptococcus pneumoniae urinary antigen test in healthy children with nasopharyngeal pneumococcal carriage

We evaluated the influence of colonization with pneumococci on the results of Streptococcus pneumoniae urinary antigen detection assay by testing 23 healthy children aged 1-3 years in one nursery. Nasopharyngeal swab specimens for culture and urine samples for antigen detection test were obtained. 7 of 12 children who were nasopharyngeal carriers of pneumococci had a positive result of the urine antigen test. 3 of 11 children without pneumococci in the nasopharynx also had a positive result of the urine antigen test, who were diagnosed as having acute pneumonia within one month before this study. Thus we found that 58.3% of the children with pneumococcal carriage and 27.3% of non-carriers had false-positive test results. This test is not likely to be useful for diagnosing the etiology of childhood acute pneumococcal pneumonia.     

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.     

Antibody to capsular polysaccharides of Streptococcus pneumoniae after vaccination of human immunodeficiency virus-infected subjects with 23-valent pneumococcal vaccine.

The Centers for Disease Control recommends that, because of a greatly increased susceptibility to pneumococcal infection, all persons infected with human immunodeficiency virus (HIV) receive pneumococcal vaccine. Using an ELISA specific for antibody to capsular polysaccharide, a postvaccination antibody was evaluated to five commonly infecting serotypes of Streptococcus pneumoniae. Thirty-nine HIV-infected persons with less than or equal to 500 CD4 cells exhibited significantly fewer responses than did healthy controls; overall, only 46 (24%) of 195 possible responses were positive compared with 45 (75%) of 60 in 12 HIV-infected subjects with greater than 500 CD4 cells and 92 (74%) of 125 in 25 healthy controls (P less than .001). Subjects with less than or equal to 500 CD4 cells responded to a mean of 1.1 antigens versus a mean of 3.8 and 3.7 in those with greater than 500 CD4 cells and controls, respectively (P less than .001). There were no differences between responses in those with less than 200 and those with 200-500 CD4 cells. Within groups stratified by CD4 cell counts, further stratification by clinical status did not reveal significant differences. Since asymptomatic HIV-infected persons with less than 500 CD4 cells show abnormal responses, pneumococcal vaccine should be given when HIV infection is first detected.     

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.     

Primary and booster salivary antibody responses to a 7-valent pneumococcal conjugate vaccine in infants

Salivary anticapsular antibody responses to a 7-valent pneumococcal conjugate vaccine (7VPnC) were measured in healthy infants. Infants received diphtheria-tetanus-pertussis/Haemophilus influenzae type b (DTP/Hib; group 1), DTP/Hib and 7VPnC (group 2), or DTP and 7VPnC/Hib (group 3) at ages 2, 3 and 4 months. All children received 23-valent pneumococcal polysaccharide vaccine at age 13 months. Salivary IgA and IgG responses to primary immunizations were generally poor. IgA mean concentrations at age 5 months were higher in the treatment groups than in control subjects for serotype 14 only (P<.001). At age 13-14 months, there were marked increases in IgA (mean fold difference, 3.7-4.9) and IgG (mean fold difference, 4. 1-11.7) levels for serotypes 4, 9V, 14, and 19F and serotypes 4, 18C, 19F, and 23F, respectively, in the treatment groups. This contrasts with low IgA (1.2 and 1.4) and IgG (1.3 and 2.2) mean fold differences for non-7VPnC serotypes 1 and 5. The results suggest that 7VPnC primes for mucosal memory responses in infants.     

Serotyping and multilocus sequence typing of Streptococcus pneumoniae isolates from the blood and posterior nares of Japanese children prior to the introduction of 7-valent pneumococcal conjugate vaccine

In Japan, the 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2010. To assess the effects of PCV7 on invasive pneumococcal infection in children, a population-based prospective survey has been conducted in 10 prefectures. As a part of the study, blood and nasopharyngeal isolates from children admitted to the Shibata Hospital, Niigata Prefecture, were analyzed for determining the serotypes, their susceptibilities to antimicrobial agents, and multilocus sequence types. Sixteen blood isolates were obtained from October 2007 to December 2009. Sixty-three nasopharyngeal isolates were obtained from the posterior nares of 118 children with pneumonia from April to September 2008. The coverage rates of the blood and nasopharyngeal isolates for PCV7 were 81.3% and 57.1%, respectively. Although none of these children had received PCV7, serotype 19A isolates were recovered from 12.5% (2/16) of the blood samples and 12.7% (8/63) of the nasopharyngeal samples. The sequence type of a nasopharyngeal isolate of serotype 19A was ST320, and the minimum inhibitory concentration of penicillin G was 4 μg/mL. In addition to the continuous prospective survey of pneumococcal infection, early introduction of the 13-valent conjugate vaccine, in which the 19A conjugate is included, will be necessary in Japan.     

Marked differences in pneumococcal carriage and resistance patterns between day care centers located within a small area.

Carriage rates of Streptococcus pneumoniae and their antibiotic resistance, capsular types, and genetic patterns were studied among 264 children aged 12-35 months attending 8 day care centers located within a 2.5-mile radius in the same city. Nasopharyngeal cultures were obtained within a 2-month interval from all 264 children. Significant differences in each of the studied characteristics were found between day care centers, and each day care center had a unique pattern of the carried pneumococci. Our findings show that day care centers are independent microenvironments and emphasize their role in the transmission and augmentation of antibiotic-resistant S. pneumoniae in the community.     

Antibody responses to nasopharyngeal carriage of Streptococcus pneumoniae in adults: a longitudinal household study

BACKGROUND: Natural immunity to Streptococcus pneumoniae is thought to be induced by exposure to S. pneumoniae or cross-reactive antigens. No longitudinal studies of carriage of and immune responses to S. pneumoniae have been conducted using sophisticated immunological laboratory techniques. METHODS: We enrolled 121 families with young children into this study. Nasopharyngeal (NP) swabs were collected monthly for 10 months from all family members and were cultured in a standard fashion. Cultured S. pneumoniae isolates were serotyped. At the beginning (month 0) and end (month 10) of the study, venous blood was collected from family members >18 years old. Serotype-specific antipolysaccharide immunoglobulin G (IgG) and functional antibody and antibodies to pneumolysin, pneumococcal surface protein A (PspA), and pneumococcal surface antigen A (PsaA) were measured in paired serum samples. RESULTS: Levels of anticapsular IgG increased significantly after carriage of serotypes 9V, 14, 18C, 19F, and 23F by an individual or family member. For serotype 14, a higher level of anticapsular IgG at the beginning of the study was associated with reduced odds of carriage (P = .006). There was a small (approximately 20%) but significant increase in titers of antibodies to PsaA and pneumolysin but no change in titers of antibody to PspA. CONCLUSIONS: Adults respond to NP carriage by mounting anticapsular and weak antiprotein antibody responses, and naturally induced anticapsular IgG can prevent carriage.     

Carriage of internationally spread clones of Streptococcus pneumoniae with unusual drug resistance patterns in children attending day care centers in Lisbon, Portugal

Over half (259/503) of drug-resistant (DR) pneumococci colonizing healthy children attending day care centers in Lisbon were identified by molecular typing methods as representatives of several internationally spread clones. These included the 2 penicillin-resistant pandemic Spanish/USA and French/Spanish clones (21% of all DR pneumococci) and 5 new lineages with unusual antibiotypes (accounting for an additional 30% of all DR pneumococci). The most characteristic feature of the latter group was the high frequency of resistance to macrolides and tetracycline and very low or no resistance to penicillin. These observations provide support for the notion that the nasopharyngeal flora of children in day care centers may be a global reservoir of worldwide prevalent strains of DR pneumococci.     

Serotype changes and antimicrobial nonsusceptibility rates of invasive and non-invasive Streptococcus pneumoniae isolates after implementation of 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in Bulgaria

The 10-valent pneumococcal conjugate vaccine (PCV10) has been included in Bulgarian Childhood Immunization Program since 2010. This study aimed to assess serotype distribution and antimicrobial resistance of 198 invasive and non-invasive Streptococcus pneumoniae strains that had been isolated in Bulgaria during 2011–2016 from patients with invasive (IPD) and non-invasive (NIPD) pneumococcal diseases. The most common invasive serotypes were 3 (10.1%), 19F (4.0%), and 7F (3.0%). A significant decrease in the proportion of invasive vaccine types (VTs) from 64.2% to 35.2% was found in comparison with pre-vaccine era. The most common serotypes among middle ear fluids were 3, 19A and 19F (5.6% each), and VTs fell down from 66.4% to 40.0% in post-PCV10 period. Among respiratory isolates, the most prevalent serotypes were some emergent serotypes such as 15A/B/C (5.0%), 19A, and 6C (4.0% each). VTs decreased significantly (16.3%) among vaccinated children compared to unvaccinated children and adults (44.0%). Two non-VTs (19A and 6C) have increased significantly more (p < 0.05) in vaccinated children than in unvaccinated patients. The rates of antibiotic nonsusceptible S. pneumoniae in Bulgaria remained high in post-PCV10 era. Among all source of isolates, antimicrobial nonsusceptibility rates were: oral penicillin – 46.5%, trimethoprim-sulfamethoxazole – 45.4%, erythromycin – 43.9%, tetracycline – 37.4%, and multidrug-resistance (MDR) was 44%. The most common MDR serotypes were 19F, 19A, 6A/C, 15A/B/C and 23A. Our results proved that PCV10 vaccination substantially reduced VTs pneumococcal IPD and NIPD. There has been a shift in the distribution of S. pneumoniae serotypes mostly in vaccinated children but also in the whole population and strong serotype-specific antibiotic resistance was observed after vaccine implementation. Therefore, it is important to continue monitoring serotype changes and pneumococcal resistance among all patient ages in addition to aid in determining the long-term effectiveness of PCV10 interventions.