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.

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.

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.

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.

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.

Changes in molecular epidemiology of streptococcus pneumoniae causing meningitis following introduction of pneumococcal conjugate vaccination in England and Wales.

The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in September 2006 has markedly reduced the burden of invasive pneumococcal disease (IPD) including meningitis in England and Wales. This study examined changes in the molecular epidemiology of pneumococcal isolates causing meningitis from July 2004 to June 2009. The Health Protection Agency conducts enhanced pneumococcal surveillance in England and Wales. In addition to serotyping, pneumococcal isolates causing meningitis were genotyped by multilocus sequence typing (MLST). A total of 1,030 isolates were both serotyped and genotyped over the 5-year period. Fifty-two serotypes, 238 sequence types (STs), and 87 clonal complexes were identified, with no significant difference in the yearly Simpson's diversity index values (range, 0.974 to 0.984). STs commonly associated with PCV7 serotypes declined following PCV implementation, with a proportionally greater decline in ST124 (commonly associated with serotype 14). No other ST showed significant changes in distribution, even within individual serotypes. Replacement disease following PCV7 introduction was mainly due to serotypes 1, 3, 7F, 19A, 22F, and 33F through clonal expansion. A single instance of possible capsule switching was identified where one ST4327 clone expressed a serotype 14 capsule in 2005 and a serotype 28A capsule in 2009. In 2008 to 2009, ST191 (7F) became the most prevalent clone causing meningitis (10.3%). Case fatality (145 fatalities/1,030 cases; 14.1%) was high across all age groups and serotype groups. Thus, the introduction of PCV7 resulted in an increase in non-PCV7 serotypes, including some not covered by the 13-valent vaccine, such as serotypes 22F and 33F, emphasizing the importance of long-term epidemiological and molecular surveillance.

Impact of Haemophilus influenzae Type b conjugate vaccine in Mongolia: prospective population-based surveillance, 2002-2010.

OBJECTIVES: Bacterial meningitis is associated with high mortality and long-term complications. This study assessed the impact of Haemophilus influenzae type b (Hib) conjugate vaccine on childhood bacterial meningitis in Ulaanbaatar, Mongolia. STUDY DESIGN: Prospective, active, population-based surveillance for suspected meningitis in children aged 2-59 months was conducted (February 2002-January 2011) in 6 hospitals. Clinical data, blood, and cerebrospinal fluid were collected. The impact of Hib conjugate vaccine was assessed by comparing Hib and all cause meningitis data in the 3 years preceding pentavalent conjugate vaccine implementation (2002-2004) with 3 years postimplementation (2008-2010). RESULTS: Five hundred eleven cases of suspected meningitis were identified from 2002-2011. Pentavalent conjugate vaccine coverage in December 2005 in Ulaanbaatar city was 97%. The proportion of suspected cases confirmed as Hib meningitis decreased from 25% (50/201) in the prevaccination era to 2% (4/193) in the postvaccination era (P < .0001). The annual incidence of Hib decreased from 28 cases per 100,000 children in 2002-2005 to 2 per 100,000 in 2008-2010 (P < .0001). CONCLUSIONS: This article demonstrates the marked impact of Hib conjugate vaccine introduction on meningitis in Mongolia. It is important to sustain this surveillance system to monitor the long-term impact of Hib conjugate vaccine, as well as other interventions such as pneumococcal and meningococcal vaccines.

Effects of pneumococcal conjugate vaccines on reducing the risk of respiratory disease associated with coronavirus infection.

Pneumococcal conjugate vaccines (PCVs) provide protection against vaccine-type pneumococcal disease in both children and adults. Growing evidence suggests that PCVs also reduce pneumonia and lower respiratory tract infections (LRTIs) more broadly, including protecting against viral-associated respiratory diseases. In this short narrative review, we highlight clinical studies investigating whether PCVs might have a role in reducing coronavirus disease, both those caused by endemic human coronaviruses (HCoVs) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). These studies include two randomized controlled trials assessing HCoV-associated pneumonia, one each in children and older adults, and two observational studies of PCV13 effectiveness against HCoV-associated LRTI and COVID-19 in adults. We discuss possible mechanisms for PCV protection including preventing viral pneumococcal co-infections and the possibility that pneumococci in the upper respiratory tract might modify the host immune response to SARS-CoV-2. Lastly, we identify knowledge gaps and further questions on the potential role of PCVs during the COVID-19 pandemic.

Systematic Literature Review of the Epidemiological Characteristics of Pneumococcal Disease Caused by the Additional Serotypes Covered by the 20-Valent Pneumococcal Conjugate Vaccine.

Higher valency pneumococcal conjugate vaccines (PCV15 and PCV20) have been developed to address the disease burden of current non-vaccine serotypes. This review describes the epidemiological characteristics of serotypes beyond PCV13 (serotypes 8, 10A, 11A, 12F, 15B/C, 22F, and 33F; PCV20nonPCV13 serotypes). Peer-reviewed studies published between 1 January 2010 (the year PCV13 became available) and 18 August 2020 were systematically reviewed (PROSPERO number: CRD42021212875). Data describing serotype-specific outcomes on disease proportions, incidence, severity, and antimicrobial non-susceptibility were summarized for individual and aggregate PCV20nonPCV13 serotypes by age group and by type and duration of pediatric PCV immunization program. Of 1168 studies, 127 (11%) were included in the analysis. PCV20nonPCV13 serotypes accounted for 28% of invasive pneumococcal disease (IPD), although the most frequent serotypes differed between children (10A, 15B/C) and adults (8, 12F, 22F). In children, serotype 15B/C tended to be more frequently associated with pneumococcal meningitis and acute otitis media; in adults, serotype 8 was more frequently associated with pneumonia and serotype 12F with meningitis. Serotypes 10A and 15B/C in children and 11A and 15B/C in adults were often associated with severe IPD. Serotype 15B/C was also among the most frequently identified penicillin/macrolide non-susceptible PCV20nonPCV13 serotypes. These results could inform decision making about higher valency PCV choice and use.

Distribution of serotypes causing invasive pneumococcal disease in older adults from high-income countries and impact of pediatric and adult vaccination policies.

BACKGROUND: Neither indirect protection through use of 13-valent and 10-valent pneumococcal conjugate vaccines (PCV13 and PCV10) in pediatric National Immunization Programs (NIPs) nor direct vaccination with the 23-valent polysaccharide vaccine have eliminated vaccine serotype invasive pneumococcal disease (IPD) in older adults. Vaccinating older adults with higher-valency PCV15 and PCV20 could address remaining IPD due to pediatric PCV serotypes plus additional IPD due to serotypes included in these vaccines. METHODS: We collected serotype-specific IPD data in older adults (≥65 years in most countries), from national or regional surveillance systems or hospital networks of 33 high-income countries. Data were from official government websites, online databases, surveillance system reports, published literature, and personal communication with in-country investigators. Average percentages of IPD serotypes were calculated. RESULTS: Among 52,905 cases of IPD with a serotype identified, PCV13 serotypes accounted for 33.7% of IPD (55.8% and 30.6% for countries with PCV10 and PCV13 in the pediatric NIP), most commonly serotypes 3 (14.9%) and 19A (7.0%). PCV15 and PCV20 would cover an additional 10.4% and 32.9% of older adult IPD beyond PCV13 serotypes (PCV10 countries: 7.7% and 23.3%; PCV13 countries: 10.6% and 34.6%). The most common of these additional serotypes were 8 (9.9%), 22F (7.9%), 12F (4.6%), and 11A (3.3%). PPSV23 policies for older adults were not correlated with lower IPD percentages due to PPSV23 serotypes. CONCLUSIONS: Vaccinating older adults with higher-valency PCVs, especially PCV20, could substantially reduce the remaining IPD burden in high-income countries, regardless of current PCV use in pediatric NIPs and adult PPSV23 policies.

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

INTRODUCTION: Fifteen 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. METHODS: We conducted a literature search in PubMed and Google Scholar and screened 525 studies using a standardized evaluation framework. RESULTS: Nine 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. CONCLUSIONS: Overall, 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.

Evaluation of the World Health Organization Global Invasive Bacterial Vaccine-Preventable Disease (IB-VPD) Surveillance Network's Laboratory External Quality Assessment Programme, 2014-2019.

Introduction. In 2009, the World Health Organization (WHO) established the Global Invasive Bacterial Vaccine Preventable Disease (IB-VPD) Surveillance Network (GISN) to monitor the global burden and aetiology of bacterial meningitis, pneumonia and sepsis caused by Haemophilus influenzae (Hi), Neisseria meningitidis (Nm) and Streptococcus pneumoniae (Sp).Hypothesis/Gap Statement. The GISN established an external quality assessment (EQA) programme for the characterization of Hi, Nm and Sp by culture and diagnostic PCR.Aim. To assess the performance of sentinel site laboratories (SSLs), national laboratories (NLs) and regional reference laboratories (RRLs) between 2014 and 2019 in the EQA programme.Methodology. Test samples consisted of bacterial smears for Gram-staining, viable isolates for identification and serotyping or serogrouping (ST/SG), plus simulated cerebrospinal fluid (CSF) samples for species detection and ST/SG by PCR. SSLs and NLs were only required to analyse the slides for Gram staining and identify the species of the live isolates. RRLs, and any SLs and NLs that had the additional laboratory capacity, were also required to ST/SG the viable isolates and analyse the simulated CSF samples.Results. Across the period, 69-112 SS/NL labs and eight or nine RRLs participated in the EQA exercise. Most participants correctly identified Nm and Sp in Gram-stained smears but were less successful with Hi and other species. SSLs/NLs identified the Hi, Nm and Sp cultures well and also submitted up to 56 % of Hi, 62 % of Nm and 33 % of Sp optional ST/SG results each year. There was an increasing trend in the proportion of correct results submitted over the 6 years for Nm and Sp. Some SSLs/NLs also performed the optional detection and ST/SG of the three organisms by PCR in simulated CSF from 2015 onwards; 89-100 % of the CSF samples were correctly identified and 76-93 % of Hi-, 90-100 % of Nm- and 75-100 % of Sp-positive samples were also correctly ST/SG across the distributions. The RRLs performed all parts of the EQA to a very high standard, with very few errors across all aspects of the EQA.Conclusion. The EQA has been an important tool in maintaining high standards of laboratory testing and building of laboratory capacity in the GISN.

Invasive Haemophilus influenzae serotype e and f disease, England and Wales.

Haemophilus influenzae infection causes serious invasive disease, but incidence of the most virulent serotype, Hib, has dropped since introduction of routine Hib vaccination. In England and Wales, the incidence of 2 other serotypes, Hie and Hif, is increasing; during 2001-2010, there was an 11.0% year-on-year increase in Hif and a 7.4% increase in Hie. In 2009-2010, Hif incidence was 0.090/100,000 persons and Hie incidence 0.030/100,000, with higher rates among infants and older adults. Hie had a more severe clinical course; although outcome at 6 months was comparable for the 2 serotypes, case-fatality rate within 7 days of diagnosis was higher for Hie, even after adjustment for age and comorbidities. Multilocus sequence typing revealed a single major circulating clone for both Hif (sequence type 124; 89/99 isolates, 90%) and Hie (sequence type 18; 21/33, 64%), but no association between type and clinical disease or outcome was found.