Distribution of Serotypes Causing Invasive Pneumococcal Disease in Children From High-Income Countries and the Impact of Pediatric Pneumococcal Vaccination.

BACKGROUND: The introduction and adoption of pneumococcal conjugate vaccines (PCVs) into pediatric national immunization programs (NIPs) has led to large decreases in invasive pneumococcal disease (IPD) incidence caused by vaccine serotypes. Despite these reductions, the global IPD burden in children remains significant. METHODS: We collected serotype-specific IPD data from surveillance systems or hospital networks of all 30 high-income countries that met inclusion criteria. Data sources included online databases, surveillance system reports, and peer-reviewed literature. Percentage of serotyped cases covered were calculated for all countries combined and by PCV type in the pediatric NIP. RESULTS: We identified 8012 serotyped IPD cases in children <5 or ≤5 years old. PCV13 serotype IPD caused 37.4% of total IPD cases, including 57.1% and 25.2% for countries with PCV10 or PCV13 in the pediatric NIP, respectively, most commonly due to serotypes 3 and 19A (11.4% and 13.3%, respectively, across all countries). In PCV10 countries, PCV15 and PCV20 would cover an additional 45.1% and 55.6% of IPD beyond serotypes contained in PCV10, largely due to coverage of serotype 19A. In PCV13 countries, PCV15 and PCV20 would cover an additional 10.6% and 38.2% of IPD beyond serotypes contained in PCV13. The most common IPD serotypes covered by higher valency PCVs were 10A (5.2%), 12F (5.1%), and 22F and 33F (3.5% each). CONCLUSIONS: Much of the remaining IPD burden is due to serotypes included in PCV15 and PCV20. The inclusion of these next generation PCVs into existing pediatric NIPs may further reduce the incidence of childhood IPD.

Long-Term effects of COVID-19: a review of current perspectives and mechanistic insights.

Although SARS-CoV-2, responsible for COVID-19, is primarily a respiratory infection, a broad spectrum of cardiac, pulmonary, neurologic, and metabolic complications can occur. More than 50 long-term symptoms of COVID-19 have been described, and as many as 80% of patients may develop ≥1 long-term symptom. To summarize current perspectives of long-term sequelae of COVID-19, we conducted a PubMed search describing the long-term cardiovascular, pulmonary, gastrointestinal, and neurologic effects post-SARS-CoV-2 infection and mechanistic insights and risk factors for the above-mentioned sequelae. Emerging risk factors of long-term sequelae include older age (≥65 years), female sex, Black or Asian race, Hispanic ethnicity, and presence of comorbidities. There is an urgent need to better understand ongoing effects of COVID-19. Prospective studies evaluating long-term effects of COVID-19 in all body systems and patient groups will facilitate appropriate management and assess burden of care. Clinicians should ensure patients are followed up and managed appropriately, especially those in at-risk groups. Healthcare systems worldwide need to develop approaches to follow-up and support patients recovering from COVID-19. Surveillance programs can enhance prevention and treatment efforts for those most vulnerable.

The Global Landscape of Pediatric Bacterial Meningitis Data Reported to the World Health Organization-Coordinated Invasive Bacterial Vaccine-Preventable Disease Surveillance Network, 2014-2019.

BACKGROUND: The World Health Organization (WHO) coordinates the Global Invasive Bacterial Vaccine-Preventable Diseases (IB-VPD) Surveillance Network to support vaccine introduction decisions and use. The network was established to strengthen surveillance and laboratory confirmation of meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. METHODS: Sentinel hospitals report cases of children <5 years of age hospitalized for suspected meningitis. Laboratories report confirmatory testing results and strain characterization tested by polymerase chain reaction. In 2019, the network included 123 laboratories that follow validated, standardized testing and reporting strategies. RESULTS: From 2014 through 2019, >137 000 suspected meningitis cases were reported by 58 participating countries, with 44.6% (n = 61 386) reported from countries in the WHO African Region. More than half (56.6%, n = 77 873) were among children <1 year of age, and 4.0% (n = 4010) died among those with reported disease outcome. Among suspected meningitis cases, 8.6% (n = 11 798) were classified as probable bacterial meningitis. One of 3 bacterial pathogens was identified in 30.3% (n = 3576) of these cases, namely S. pneumoniae (n = 2177 [60.9%]), H. influenzae (n = 633 [17.7%]), and N. meningitidis (n = 766 [21.4%]). Among confirmed bacterial meningitis cases with outcome reported, 11.0% died; case fatality ratio varied by pathogen (S. pneumoniae, 12.2%; H. influenzae, 6.1%; N. meningitidis, 11.0%). Among the 277 children who died with confirmed bacterial meningitis, 189 (68.2%) had confirmed S. pneumoniae. The proportion of pneumococcal cases with pneumococcal conjugate vaccine (PCV) serotypes decreased as the number of countries implementing PCV increased, from 77.8% (n = 273) to 47.5% (n = 248). Of 397 H. influenzae specimens serotyped, 49.1% (n = 195) were type b. Predominant N. meningitidis serogroups varied by region. CONCLUSIONS: This multitier, global surveillance network has supported countries in detecting and serotyping the 3 principal invasive bacterial pathogens that cause pediatric meningitis. Streptococcus pneumoniae was the most common bacterial pathogen detected globally despite the growing number of countries that have nationally introduced PCV. The large proportions of deaths due to S. pneumoniae reflect the high proportion of meningitis cases caused by this pathogen. This global network demonstrated a strong correlation between PCV introduction status and reduction in the proportion of pneumococcal meningitis infections caused by vaccine serotypes. Maintaining case-based, active surveillance with laboratory confirmation for prioritized vaccine-preventable diseases remains a critical component of the global agenda in public health.The World Health Organization (WHO)-coordinated Invasive Bacterial Vaccine-Preventable Disease (IB-VPD) Surveillance Network reported data from 2014 to 2019, contributing to the estimates of the disease burden and serotypes of pediatric meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis.

Systematic literature review of the impact and effectiveness of monovalent meningococcal C conjugated vaccines when used in routine immunization programs.

BACKGROUND: Monovalent meningococcal C conjugate vaccine (MCCV) was introduced into the routine immunization program in many countries in Europe and worldwide following the emergence of meningococcal serogroup C (MenC) in the late 1990s. This systematic literature review summarizes the immediate and long-term impact and effectiveness of the different MCCV vaccination schedules and strategies employed. METHODS: We conducted a systematic literature search for peer-reviewed, scientific publications in the databases of MEDLINE (via PubMed), LILACS, and SCIELO. We included studies from countries where MCCV have been introduced in routine vaccination programs and studies providing the impact and effectiveness of MCCV published between 1st January 2001 and 31st October 2017. RESULTS: Forty studies were included in the review; 30 studies reporting impact and 17 reporting effectiveness covering 9 countries (UK, Spain, Italy, Canada, Brazil, Australia, Belgium, Germany and the Netherlands). Following MCCV introduction, significant and immediate reduction of MenC incidence was consistently observed in vaccine eligible ages in all countries with high vaccine uptake. The reduction in non-vaccine eligible ages (especially population > 65 years) through herd protection was generally observed 3-4 years following introduction. Vaccine effectiveness (VE) was mostly assessed through screening methods and ranged from 38 to 100%. The VE was generally highest during the first year after vaccination and waned over time. The VE was better maintained in countries employing catch-up campaigns in older children and adolescents, compared to routine infant only schedules. CONCLUSIONS: MCCV were highly effective, showing a substantial and sustained decrease in MenC invasive meningococcal disease. The epidemiology of meningococcal disease is in constant transition, and some vaccination programs now include adolescents and higher valent vaccines due to the recent increase in cases caused by serogroups not covered by MCCV. Continuous monitoring of meningococcal disease is essential to understand disease evolution in the setting of different vaccination programs.

Nontypeable Haemophilus influenzae and chronic obstructive pulmonary disease: a review for clinicians.

Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality worldwide. In the lower airways of COPD patients, bacterial infection is a common phenomenon and Haemophilus influenzae is the most commonly identified bacteria. Haemophilus influenzae is divided into typeable and nontypeable (NTHi) strains based on the presence or absence of a polysaccharide capsule. While NTHi is a common commensal in the human nasopharynx, it is associated with considerable inflammation when it is present in the lower airways of COPD patients, resulting in morbidity due to worsening symptoms and increased frequency of COPD exacerbations. Treatment of lower airway NTHi infection with antibiotics, though successful in the short term, does not offer long-term protection against reinfection, nor does it change the course of the disease. Hence, there has been much interest in the development of an effective NTHi vaccine. This review will summarize the current literature concerning the role of NTHi infections in COPD patients and the consequences of using prophylactic antibiotics in patients with COPD. There is particular focus on the rationale, findings of clinical studies and possible future directions of NTHi vaccines in patients with COPD.

Childhood Deaths Attributable to Invasive Pneumococcal Disease in England and Wales, 2006-2014.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) are highly effective in preventing invasive pneumococcal disease (IPD), but deaths due to IPD still occur. We aimed to describe children who died of IPD since PCV introduction in England and Wales. METHODS: Public Health England conducts enhanced IPD surveillance in England and Wales. IPD cases in PCV-eligible children aged <5 years (born since 4 September 2004 and diagnosed between 4 September 2006 and 3 September 2014) were actively followed up by postal questionnaires and, for fatal cases, detailed information was requested prospectively from multiple sources. RESULTS: During the 8-year period, there were 3146 IPD cases and 150 IPD-related deaths (case fatality rate, 4.8%). Overall, 132 isolates from fatal cases were serotyped (88%) and 35 distinct serotypes were identified, with no serotype predominance. Most deaths occurred in children aged <1 year (88/150 [59%]) and 1-year-olds (36/150 [24%]). One-third (53/150 [35%]) had a known risk factor for IPD. Clinical presentation varied with age but not by serotypes in the different conjugate vaccines. Meningitis was diagnosed in nearly half the fatal cases (71/150 [47%]). The IPD-related mortality rate declined after 7-valent PCV introduction from 1.25/100000 children in 2006-2007 to 0.60/100000 in 2009-2010, with a further reduction following 13-valent PCV introduction from April 2010 to 0.39/100000 in 2013-2014 (14 deaths; incidence rate ratio, 0.31 [95% confidence interval, .16-.61]; P = .0003), when most deaths were due to nonvaccine serotypes or in neonates. CONCLUSIONS: Most fatal IPD cases are currently not vaccine-preventable. Additional strategies will be required to reduce childhood pneumococcal deaths in countries with established pneumococcal vaccination programs.

Characteristics and Serotype Distribution of Childhood Cases of Invasive Pneumococcal Disease Following Pneumococcal Conjugate Vaccination in England and Wales, 2006-2014.

Background: The 7-valent and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13, respectively) are highly effective in preventing invasive pneumococcal disease (IPD) caused by vaccine serotypes. Vaccine failure (vaccine-type IPD after age-appropriate immunization) is rare. Little is known about the risk, clinical characteristics, or outcomes of PCV13 compared to PCV7 vaccine failure. Methods: Public Health England conducts IPD surveillance and provides a national reference service for serotyping pneumococcal isolates in England and Wales. We compared the epidemiology, rates, risk factors, serotype distribution, clinical characteristics, and outcomes of IPD in children with PCV13 and PCV7 vaccine failure. Results: A total of 163 episodes of PCV failure were confirmed in 161 children over 8 years (4 September 2006 to 3 September 2014) in 10 birth cohorts. After 3 vaccine doses, PCV7 and PCV13 failure rates were 0.19/100000 (95% confidence interval [CI], .10-.33 [57 cases]) and 0.66/100000 (95% CI, .44-.95 [104 cases]) vaccinated person-years, respectively. Children with PCV13 failure were more likely to be healthy (87/105 [82.9%] vs 37/56 [66.1%]; P = .02), present with bacteremic lower respiratory tract infection (LRTI) (61/105 [58.1%] vs 11/56 [19.6%]; P < .001), and develop empyema (41/61 [67.2%] vs 1/11 [9.1%]; P < .001) compared to PCV7 failures. Serotypes 3 (n = 38 [36.2%]) and 19A (n = 30 [28.6%]) were responsible for most PCV13 failures. Six children died (4% [95% CI, 1%-8%]), including 5 with comorbidities. Conclusions: PCV failure is rare and, compared to PCV7 serotypes, the additional PCV13 serotypes are more likely to cause bacteremic LRTI and empyema in healthy vaccinated children.

Neonatal invasive Haemophilus influenzae disease in England and Wales: epidemiology, clinical characteristics, and outcome.

BACKGROUND: Nontypeable Haemophilus influenzae (NTHi) frequently causes noninvasive upper respiratory tract infections in children but can cause invasive disease, mainly in older adults. An increased burden of invasive NTHi disease in the perinatal period has been reported by a number of studies. Here we describe the epidemiology, clinical characteristics, and outcome of neonatal invasive H. influenzae disease in England and Wales over a 5-year period. METHODS: Public Health England conducts enhanced national surveillance of invasive H. influenzae disease in England and Wales. Detailed clinical information was obtained for all laboratory-confirmed cases in infants aged ≤31 days during 2009-2013. RESULTS: Overall, 118 live-born neonates had laboratory-confirmed invasive H. influenzae disease: 115 (97%) were NTHi, 2 were serotype f, and 1 was serotype b. NTHi was isolated within 48 hours of birth (early-onset) in 110 of 115 (96%) cases, and 70 of 110 (64%) presented with septicemia. Only 17 mothers (15%) had suspected bacterial infection requiring antibiotics during labor. Few (8/110 [7%]) neonates had comorbidities. The incidence of early-onset NTHi increased exponentially with prematurity, from 0.9 per 100 000 (95% confidence interval [CI], .6-1.4) in term neonates to 342 per 100 000 (95% CI, 233.9-482.7) in neonates born at <28 weeks' gestation (incidence rate ratio, 365 [95% CI, 205-659]; P < .001). Case fatality for early-onset NTHi was 19% (21/110); each additional gestational week reduced the odds of dying by 21% (odds ratio, 0.79 [95% CI, .69-.90]; P < .01). A quarter of neonates who survived experienced long-term complications. CONCLUSIONS: Early-onset neonatal NTHi disease is strongly associated with premature birth and causes significant morbidity and mortality.

Antibody concentrations against the infecting serotype in vaccinated and unvaccinated children with invasive pneumococcal disease in the United Kingdom, 2006-2013.

BACKGROUND: This study aimed to estimate, following invasive pneumococcal disease (IPD), the proportion of children with protective immunoglobulin G (IgG) concentrations against the infecting serotype compared with other vaccine serotypes, and to assess risk of recurrent IPD. METHODS: Pneumococcal antibody concentrations were available for 413 children with vaccine-type IPD diagnosed during 2006-2013. We compared serotype-specific IgG concentrations against the infecting vs other vaccine serotypes, after adjusting for confounders such as age using multilevel analyses. RESULTS: After IPD, a higher proportion of vaccine-naive children had IgG concentrations ≥0.35 µg/mL against their infecting serotype than other vaccine serotypes (51% vs 36%; P < .001). In contrast, among children immunized with pneumococcal conjugate vaccine (PCV) both before and after IPD, the proportion with IgG concentrations ≥0.35 µg/mL against the infecting serotype was lower compared with other vaccine serotypes (71% vs 98%; P < .001). These children also had lower IgG geometric mean concentrations (GMCs) against the infecting serotype (2.22 µg/mL) vs other vaccine serotypes (15.64 µg/mL) in multilevel models (IgG GMC ratio, 0.24; 95% confidence interval, .18-.32), although their IgG GMC was higher compared with vaccine-naive children. Vaccinated children with IgG concentrations <0.35 µg/mL against their infecting serotype generally remained unresponsive despite further vaccine doses. However, recurrent IPD with the same infecting serotype was rare (7/3030 children [0.2%]) and not associated with unresponsiveness. CONCLUSIONS: Vaccination with PCV before and/or after IPD was associated with lower IgG concentrations against the infecting serotype compared with other vaccine serotypes, but recurrent IPD was rare. Further studies are needed to understand this phenomenon in immunized children.

Impact of infant 13-valent pneumococcal conjugate vaccine on serotypes in adult pneumonia.

Infant 13-valent pneumococcal conjugate vaccination (PCV13) was introduced to the UK in 2010. Its impact on serotypes implicated in adult non-bacteraemic pneumococcal pneumonia is not known. Beginning in 2008, a 5-year prospective cohort study of adults admitted to hospital with community-acquired pneumonia (CAP) was conducted. Pneumococcal serotype was established using a validated multiplex immunoassay (Bio-Plex; Bio-Rad, Hercules, CA, USA). The overall incidence for hospitalised CAP and pneumococcal CAP was 79.9 (95% CI 76.6-83.3) and 23.4 (95% CI 21.6-25.3) per 100,000 population, respectively. A decline in CAP (incidence rate ratio (IRR) per year 0.96, 95% CI 0.94-0.99; p=0.016) and pneumococcal CAP (IRR per year 0.84, 95% CI 0.80-0.89; p<0.001) was observed over the 5-year period of the study. Between the pre- and post-PCV13 periods of the study, the incidence of CAP due to serotypes included in the PCV7 declined by 88% (IRR 0.12, 95% CI 0.08-0.20; p<0.001), and CAP due to the additional 6 serotypes in PCV13 declined by 30% (IRR 0.70, 95% CI 0.51-0.96; p=0.024). Incidence of adult pneumococcal pneumonia declined over the last 5 years, with serotypes included in PCV13 declining post-PCV13 introduction, indicating early herd protection effects from PCV13 infant vaccination on adult non-bacteraemic disease. These effects may accrue over the coming years with implications for national pneumococcal vaccination policies in adults.

Invasive pneumococcal disease, comorbidities, and polysaccharide vaccine use in children aged 5-15 years in England and Wales.

BACKGROUND: In the United Kingdom, the 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended in addition to routine pneumococcal conjugate vaccination for at-risk children aged ≥2 years. This study describes the epidemiology, serotype distribution, clinical characteristics, vaccination status, and reasons for nonvaccination in children aged 5-15 years with invasive pneumococcal disease (IPD). METHODS: Public Health England conducts enhanced national surveillance of IPD in England and Wales. In 2012, general practitioners (GPs) were contacted to complete a questionnaire for children aged 5-15 years with laboratory-confirmed IPD diagnosed during 2 epidemiological years, July 2009-June 2011. RESULTS: During 2009-2011, 447 IPD episodes occurred in 439 children (incidence, 2.2/100 000), and GPs of 423 of the 439 (96.4%) children completed the questionnaire. Comorbidity was reported in 124 (29.3%); a third each were immunocompromised or had chronic respiratory disease or other comorbidities. Pneumonia was the most common presentation (332/439 [75.6%]), and IPD-related case fatality was 1.8% (8/439). Only 26.6% (33/124) of children with comorbidities had received PPV23, and development of PPV23-type IPD was not associated with prior PPV23 vaccination (adjusted odds ratio [AOR], 1.09; 95% confidence interval [CI], .36-3.32; P = .88), even when analysis was restricted to the extra 11 PPV23 serotypes not contained in the 13-valent pneumococcal conjugate vaccine (AOR, 1.70; 95% CI, .30-9.76; P = .55). GPs of eligible but unvaccinated cases with comorbidities were mostly unaware that the child required PPV23 and/or expected pediatricians to inform them to administer the vaccine. CONCLUSIONS: Only a quarter of children with comorbidities who developed IPD had received PPV23 prior to infection. Among PPV23-vaccinated children with comorbidities, however, there was no evidence of protection against PPV23 serotypes.

Pneumococcal serotypes in adult non-invasive and invasive pneumonia in relation to child contact and child vaccination status.

BACKGROUND: On a population level, pneumococcal conjugate vaccination in children has reduced the incidence of vaccine-type disease in all age groups, including older adults. Few individual level studies have been performed describing the pneumococcal serotypes associated with adult community acquired pneumonia (CAP) and quantifying associations with child contact and child vaccination status. METHODS: Pneumococcal serotypes were determined using a validated multiplex immunoassay (Bio-Plex) in a large prospective cohort of adults hospitalised with CAP. Child (<16 years old) contact history and child pneumococcal vaccination status were obtained from patients and public health records, respectively. RESULTS: Of 1130 participants, 329 (29.1%) reported child contact, and pneumococcal infection was identified in 410 (36.3%). Pneumococcal CAP was commoner in adults with child contact (148/329 (45.0%) vs 262/801 (32.7%); adjusted OR 1.63, CI 1.25 to 2.14; p<0.001). A serotype was determined in 263 of 410 (64.1%) adults with pneumococcal CAP; 112 (42.6%) reported child contact, 38 (33.9%) with a vaccinated child. Adults in contact with a vaccinated child were significantly less likely to have vaccine-type CAP compared with adults in contact with an unvaccinated child (6 of 38 (15.8%) vs 25 of 74 (33.8%), respectively; OR 0.37, 95% CI 0.14 to 0.99; p=0.044). CONCLUSIONS: Pneumococcal aetiology in adult CAP is independently associated with child contact and implicated serotypes are influenced by child vaccination status. This is the first study to demonstrate these associations at an individual rather than population level; it affirms that 'herd protection' from childhood vaccination extends beyond adult invasive disease to pneumococcal CAP.

Risk of invasive Haemophilus influenzae infection during pregnancy and association with adverse fetal outcomes.

IMPORTANCE: Unencapsulated Haemophilus influenzae frequently causes noninvasive upper respiratory tract infections in children but can also cause invasive disease, especially in older adults. A number of studies have reported an increased incidence in neonates and suggested that pregnant women may have an increased susceptibility to invasive unencapsulated H. influenzae disease. OBJECTIVE: To describe the epidemiology, clinical characteristics, and outcomes of invasive H. influenzae disease in women of reproductive age during a 4-year period. DESIGN, SETTING, AND PARTICIPANTS: Public Health England conducts enhanced national surveillance of invasive H. influenzae disease in England and Wales. Clinical questionnaires were sent prospectively to general practitioners caring for all women aged 15 to 44 years with laboratory-confirmed invasive H. influenzae disease during 2009-2012, encompassing 45,215,800 woman-years of follow-up. The final outcome was assessed in June 2013. EXPOSURES: Invasive H. influenzae disease confirmed by positive culture from a normally sterile site. MAIN OUTCOMES AND MEASURES: The primary outcome was H. influenzae infection and the secondary outcomes were pregnancy-related outcomes. RESULTS: In total, 171 women had laboratory-confirmed invasive H. influenzae infection, which included 144 (84.2%; 95% CI, 77.9%-89.3%) with unencapsulated, 11 (6.4%; 95% CI, 3.3%-11.2%) with serotype b, and 16 (9.4%; 95% CI, 5.4%-14.7%) with other encapsulated serotypes. Questionnaire response rate was 100%. Overall, 75 of 171 women (43.9%; 95% CI, 36.3%-51.6%) were pregnant at the time of infection, most of whom were previously healthy and presented with unencapsulated H. influenzae bacteremia. The incidence rate of invasive unencapsulated H. influenzae disease was 17.2 (95% CI, 12.2-24.1; P < .001) times greater among pregnant women (2.98/100,000 woman-years) compared with nonpregnant women (0.17/100,000 woman-years). Unencapsulated H. influenzae infection during the first 24 weeks of pregnancy was associated with fetal loss (44/47; 93.6% [95% CI, 82.5%-98.7%]) and extremely premature birth (3/47; 6.4% [95% CI, 1.3%-17.5%]). Unencapsulated H. influenzae infection during the second half of pregnancy was associated with premature birth in 8 of 28 cases (28.6%; 95% CI, 13.2%-48.7%) and stillbirth in 2 of 28 cases (7.1%; 95% CI, 0.9%-23.5%). The incidence rate ratio for pregnancy loss was 2.91 (95% CI, 2.13-3.88) for all serotypes of H. influenzae and 2.90 (95% CI, 2.11-3.89) for unencapsulated H. influenzae compared with the background rate for pregnant women. CONCLUSIONS AND RELEVANCE: Among women in England and Wales, pregnancy was associated with a greater risk of invasive H. influenzae infection. These infections were associated with poor pregnancy outcomes.

Effects of PCV10 and PCV13 on pneumococcal serotype 6C disease, carriage, and antimicrobial resistance.

BACKGROUND: The cross-protection of pneumococcal conjugate vaccines (PCV) against serotype 6C is not clearly documented, although 6C represents a substantial burden of pneumococcal disease in recent years. A systematic review by the World Health Organization that covered studies through 2016 concluded that available data were insufficient to determine if either PCV10 (which contains serotype 6B but not 6A) or PCV13 (containing serotype 6A and 6B) conferred protection against 6C. METHODS: We performed a systematic review of randomized controlled trials and observational studies published between January 2010 - August 2022 (Medline/Embase), covering the direct, indirect, and overall effect of PCV10 and PCV13 against 6C invasive pneumococcal disease (IPD), non-IPD, nasopharyngeal carriage (NPC), and antimicrobial resistance (AMR). RESULTS: Of 2548 publications identified, 112 were included. Direct vaccine effectiveness against 6C IPD in children ranged between 70 and 85 % for ≥ 1 dose PCV13 (n = 3 studies), was 94 % in fully PCV13 vaccinated children (n = 2), and -14 % for ≥ 1 dose of PCV10 (n = 1). Compared to PCV7, PCV13 efficacy against 6C NPC in children was 66 % (n = 1). Serotype 6C IPD rates or NPC prevalence declined post-PCV13 in most studies in children (n = 5/6) and almost half of studies in adults (n = 5/11), while it increased post-PCV10 for IPD and non-IPD in all studies (n = 6/6). Changes in AMR prevalence were inconsistent. CONCLUSIONS: In contrast to PCV10, PCV13 vaccination consistently protected against 6C IPD and NPC in children, and provided some level of indirect protection to adults, supporting that serotype 6A but not 6B provides cross-protection to 6C. Vaccine policy makers and regulators should consider the effects of serotype 6A-containing PCVs against serotype 6C disease in their decisions.

Impact of the 7-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in infants younger than 90 days in England and wales.

BACKGROUND: Streptococcus pneumoniae is an uncommon but well-recognized cause of invasive bacterial disease in young infants. This study aimed to determine the impact of the 7-valent pneumococcal conjugate vaccine (PCV7) on invasive pneumococcal disease (IPD) in infants aged <90 days in England and Wales and describe their clinical characteristics following PCV7 introduction. METHODS: Trends in IPD among infants aged <90 days during 1998-1999 through 2009-2010 were analyzed using enhanced national surveillance data. Following PCV7 introduction, clinical information was also obtained for IPD cases in the birth cohorts eligible for vaccination. RESULTS: Prior to PCV7 introduction, IPD incidence in infants aged <90 days was 13.0 (95% confidence interval [CI], 12.0-14.0) per 100 000 live births and PCV7 serotypes accounted for 44% (154/349) of serotyped isolates. PCV7 introduction resulted in 83% (95% CI, 66%-91%, P < .001) reduction in PCV7 IPD and a declining trend in overall IPD by 2009-2010. Of the 256 cases diagnosed after PCV7 introduction, 23% (n = 60) had been born before 37 weeks' gestation. A third of cases (84/256, 33%) developed IPD in the first 48 hours of life, where 42% (35/84) were premature. Meningitis was diagnosed in 94 infants (37%) and its prevalence increased with age. Case fatality was 7% (18/256) and was higher for meningitis than nonmeningitis cases (adjusted odds ratio, 3.8 [95% CI, 1.2-12.0], P = .024). CONCLUSIONS: Young infants have benefited from PCV7 through indirect (herd) protection. Given that a third of cases occurred within 48 hours of birth, further studies should focus on risk factors for IPD in pregnancy and strategies to prevent mother-to-child transmission.

Invasive Haemophilus influenzae type b disease in England and Wales: who is at risk after 2 decades of routine childhood vaccination?

BACKGROUND: The introduction of the Haemophilus influenzae serotype b (Hib) conjugate vaccine into national immunization has led to rapid and sustained declines in invasive Hib disease incidence across all age groups. In industrialized countries with established Hib vaccination programs, however, little is known about individuals who develop invasive Hib disease. This study describes the epidemiology of invasive Hib disease in England and Wales during 2000-2012 and the clinical characteristics of laboratory-confirmed Hib cases diagnosed during 2009-2012. METHODS: Public Health England (PHE) conducts enhanced national surveillance of invasive Hib disease in England and Wales. Detailed clinical information was obtained for all laboratory-confirmed Hib cases diagnosed during 2009-2012. RESULTS: Invasive Hib disease in England and Wales has been declining since 2002, reaching its lowest incidence of 0.02 per 100 000 (14 cases) in 2012. In children aged <5 years of age, Hib incidence was 0.06 per 100 000 (2 cases), compared with 35.5 per 100 000 prior to routine Hib vaccination. Follow-up of all 106 case patients over the 4-year period revealed that most cases occurred in adults (73%) who often had preexisting medical conditions (77%) and presented with pneumonia (56%). The Hib-associated case fatality rate was 9.4% (10/106 cases). CONCLUSIONS: Control of Hib disease in England and Wales is currently the best that has been achieved since the introduction of routine Hib vaccination in 1992. Invasive Hib disease is no longer a major cause of acute bacterial meningitis in children but, instead, cases are more likely to present as pneumonia in older adults with comorbidities, similar to the less virulent nonencapsulated H. influenzae.

Invasive pneumococcal disease after routine pneumococcal conjugate vaccination in children, England and Wales.

We assessed known risk factors, clinical presentation, and outcome of invasive pneumococcal disease (IPD) in children 3-59 months of age after introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in England and Wales. During September 2006-March 2010, a total of 1,342 IPD episodes occurred in 1,332 children; 14.9% (198/1,332) had comorbidities. Compared with IPD caused by PCV7 serotypes (44/248; 17.7%), comorbidities were less common for the extra 3 serotypes in the 10-valent vaccine (15/299; 5.0%) but similar to the 3 additional PCV13 serotypes (45/336; 13.4%) and increased for the 11 extra serotypes in 23-valent polysaccharide vaccine (PPV23) (39/186; 21.0%) and non-PPV23 serotypes (38/138; 27.5%). Fifty-two (3.9%) cases resulted from PCV7 failure; 9 (0.7%) case-patients had recurrent IPD. Case-fatality rate was 4.4% (58/1,332) but higher for meningitis (11.0%) and children with comorbidities (9.1%). Thus, comorbidities were more prevalent in children with IPD caused by non-PCV13 serotypes and were associated with increased case fatality.

Serotypes associated with the development of pneumococcal para-pneumonic effusion in adults.

Serotypes 1, 3, 7F and 19A are implicated in childhood pneumococcal para-pneumonic effusion (PPE). It is not known whether the same is true for adult PPE. A prospective cohort study was conducted over a 2-year period. Consecutive adults admitted with community-acquired pneumonia (CAP) were studied. Pneumococcal serotype was identified from urine samples using a multiplex immunoassay. Of 920 patients recruited, 366 had pneumococcal CAP; 100 of these had PPE and a serotype was determined in 73 patients. Factors associated with PPE were age, pneumonia severity index score and serotype. Serotypes most associated with PPE were 1 (18 (45%) out of 40), 19A (9 (45%) out of 20) and 3 (8 (40%) out of 20). Serotypes common in childhood PPE were independently associated with adult PPE (adjusted OR 2.3; p = 0.003). Serotypes not included in the 7-valent pneumococcal conjugate vaccine (PCV) were more likely to be associated with PPE (OR 2.1; p = 0.024) compared with those in the vaccine. Serotypes included in PCV-13 were as likely to be associated with PPE as those that are not (OR 0.8; p = 0.301). Serotypes 1, 3, 7F and 19A are independently associated with adult PPE, a similar finding to childhood PPE. Serotype replacement following pneumococcal vaccine implementation may influence the spectrum of clinical disease.