Characteristics and serotype distribution of childhood cases of invasive pneumococcal disease following pneumococcal conjugate vaccination in England and Wales, 2006-14

Background The 7-valent (PCV7) and 13-valent (PCV13) pneumococcal conjugate vaccines are highly effective in preventing invasive pneumococcal disease (IPD) caused by vaccine serotypes. Vaccine failure (vaccine-type IPD after age-appropriate immunisation) 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 eight years (04 September 2006 to 03 September 2014) in ten birth cohorts. After three vaccine doses, PCV7 and PCV13 failure rates were 0.19/100,000 (95% CI, 0.10-0.33; 57 cases) and 0.66/100,000 (95% CI, 0.44-0.99; 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=0.02), present with bacteremic lower respiratory tract infection (61/105 [58.1%] vs. 11/56 [19.6%]; P<0.001) and develop empyema (41/61 [67.2%] vs. 1/11 [9.1%]; P<0.001) compared to PCV7 failures. Serotypes 3 (n=38, 36.2%) and 19A (n=30, 28.6%) were responsible for most PCV13 failures. Five children died (3.1%; 95% CI, 1.0-7.1%), including four with co-morbidities. Conclusions PCV failure is rare and, compared to PCV7 serotypes, the additional PCV13 serotypes are more likely to cause bacteremic lower respiratory tract infection and empyema in healthy vaccinated children

Invasive Haemophilus influenzae Infections after 3 Decades of Hib Protein Conjugate Vaccine Use.

Haemophilus influenzae serotype b (Hib) was previously the most common cause of bacterial meningitis and an important etiologic agent of pneumonia in children aged <5 years. Its major virulence factor is the polyribosyl ribitol phosphate (PRP) polysaccharide capsule. In the 1980s, PRP-protein conjugate Hib vaccines were developed and are now included in almost all national immunization programs, achieving a sustained decline in invasive Hib infections. However, invasive Hib disease has not yet been eliminated in countries with low vaccine coverage, and sporadic outbreaks of Hib infection still occur occasionally in countries with high vaccine coverage. Over the past 2 decades, other capsulated serotypes have been recognized increasingly as causing invasive infections. H. influenzae serotype a (Hia) is now a major cause of invasive infection in Indigenous communities of North America, prompting a possible requirement for an Hia conjugate vaccine. H. influenzae serotypes e and f are now more common than serotype b in Europe. Significant year-to-year increases in nontypeable H. influenzae invasive infections have occurred in many regions of the world. Invasive H. influenzae infections are now seen predominantly in patients at the extremes of life and those with underlying comorbidities. This review provides a comprehensive and critical overview of the current global epidemiology of invasive H. influenzae infections in different geographic regions of the world. It discusses those now at risk of invasive Hib disease, describes the emergence of other severe invasive H. influenzae infections, and emphasizes the importance of long-term, comprehensive, clinical and microbiologic surveillance to monitor a vaccine's impact

Long term impact of conjugate vaccines on haemophilus influenzae meningitis: Narrative review

H. influenzae serotype b (Hib) used to be the commonest cause of bacterial meningitis in young children. The widespread use of Hib conjugate vaccine has profoundly altered the epidemiology of H. influenzae meningitis. This short review reports on the spectrum of H. influenzae meningitis thirty years after Hib conjugate vaccine was first introduced into a National Immunization Program (NIP). Hib meningitis is now uncommon, but meningitis caused by other capsulated serotypes of H. influenzae and non-typeable strains (NTHi) should be considered. H. influenzae serotype a (Hia) has emerged as a significant cause of meningitis in Indigenous children in North America, which may necessitate a Hia conjugate vaccine. Cases of Hie, Hif, and NTHi meningitis are predominantly seen in young children and less common in older age groups. This short review reports on the spectrum of H. influenzae meningitis thirty years after Hib conjugate vaccine was first introduced into a NIP.Full Tex

Haemophilus influenzae Type b (Hib) Vaccines

It is now more than 30 years since Haemophilus influenzae type b (Hib) conjugate vaccine was first introduced into the routine infant immunization schedule in Finland, and the vaccine is now used in all European countries. From being the most important cause of bacterial meningitis, epiglottitis and other bacteraemic infections in young children, H. influenzae type b is now uncommon. The majority of invasive H. influenzae infections are now caused by non-typeable H.influenzae (NTHi), predominantly occurring in neonates and older adults with underlying comorbidities. There has been a slight increase in infections caused by other encapsulated strains, notably serotypes f (Hif) and e (Hie), which also tend to cause infection in older adults with underlying risk factors. Hib conjugate vaccine has been a remarkable success story but the persistence of small numbers of Hib infections in Europe emphasizes the importance of maintaining high vaccine coverage and continuing surveillance of all types of H. influenzae in all ages to assess the evolving epidemiology of invasive H. influenzae infections.No Full Tex

Activation Mechanism and Cellular Localization of Membrane-Anchored Alginate Polymerase in Pseudomonas aeruginosa

The exopolysaccharide alginate, produced by the opportunistic human pathogen Pseudomonas aeruginosa, confers a survival advantage to the bacterium by contributing to the formation of characteristic biofilms during infection. Membrane-anchored proteins Alg8 (catalytic subunit) and Alg44 (copolymerase) constitute the alginate polymerase that is being activated by the second messenger molecule bis-(3′, 5′)-cyclic dimeric GMP (c-di-GMP), but the mechanism of activation remains elusive. To shed light on the c-di-GMP-mediated activation of alginate polymerization in vivo, an in silico structural model of Alg8 fused to the c-di-GMP binding PilZ domain informed by the structure of cellulose synthase, BcsA, was developed. This structural model was probed by site-specific mutagenesis and different cellular levels of c-di-GMP. Results suggested that c-di-GMP-mediated activation of alginate polymerization involves amino acids residing at two loops, including H323 (loop A) and T457 and E460 (loop B), surrounding the catalytic site in the predicted model. The activities of the respective Alg8 variants suggested that c-di-GMP-mediated control of substrate access to the catalytic site of Alg8 is dissimilar to the known activation mechanism of BcsA. Alg8 variants responded differently to various c-di-GMP levels, while MucR imparted c-di-GMP for activation of alginate polymerase. Furthermore, we showed that Alg44 copolymerase constituted a stable dimer, with its periplasmic domains required for protein localization and alginate polymerization and modification. Superfolder green fluorescent protein (GFP) fusions of Alg8 and Alg44 showed a nonuniform, punctate, and patchy arrangement of both proteins surrounding the cell. Overall, this study provides insights into the c-di-GMP-mediated activation of alginate polymerization while assigning functional roles to Alg8 and Alg44, including their subcellular localization and distribution.Full Tex

Risk for invasive haemophilus influenzae infection during pregnancy and association with adverse fetal outcomes

Haemophilus influenzae is a gram-negative coccobacillus with 6 serotypes (a-f), categorized by the polysaccharide capsule. The most invasive is serotype b, and the organism can also remain unencapsulated. Routine vaccination against serotype b has decreased the incidence of the disease in all age groups. Invasive infections caused by unencapsulated H. influenzae are now relatively more common. An increased risk for invasive H. influenzae disease during pregnancy can cause serious illness in pregnant women, as well as lead to fetal death and premature delivery. This national surveillance study was undertaken to determine the epidemiology, clinical characteristics, and outcomes of invasive H. influenzae in women of reproductive age during 2009 to 2012 in England and Wales. Public Health England performs national surveillance for invasive H. influenzae disease by a combination of isolate submission, routine laboratory reporting, and clinical reporting protocols. Standardized questionnaires were sent prospectively to clinicians ∼3 months after the patients’ infections were reported. The women were aged 15 to 44 years with laboratory-confirmed invasive H. influenzae disease. From 45,215,800 woman-years of follow-up, 2568 cases of invasive infection were recorded; 1906 isolates (74.2%) were serotyped. Women of reproductive age accounted for 224 cases (8.7%) and 171 cases (9.0%) with serotyped isolates. Questionnaires were completed for all 171 cases; 144 cases (94.2%) had unencapsulated H. influenzae infection, 11 (6.4%) had serotype b, and 16 (9.4%) had other encapsulated serotypes. Sixty-five (38.4%) of the 171 women had at least 1 concurrent condition, most commonly chronic respiratory disease, malignancy, or immunosuppression; this was not associated with age at infection or serotype. Bacteremia was present in 53.8%; and pneumonia, in 29.2%, and 4% of women had meningitis. Nine women with unencapsulated H. influenzae had pelvic inflammatory disease. Four of 12 deaths were associated with H. influenzae. The case-fatality rate was 2.3%, and the strains were unencapsulated in 2 and serotype b and f in 1 each. Of the 75 women (43.9%) pregnant at diagnosis, 72 (96.0%) had unencapsulated H. influenzae; 73 (97.3%) miscarried or delivered the infant at the time of infection. The incidence rate ratio of invasive H. influenzae disease was 13 times higher in parturients compared with nonpregnant women and 17 times higher for women with unencapsulated H. influenzae (P < 0.001 for both). No women had concurrent conditions at the time of infections, and all pregnant women survived the infection. Outcomes for 75 pregnancies (77 fetuses), including 72 cases (74 fetuses) with unencapsulated disease, were recorded. Among the unencapsulated H. influenzae pregnancies, 43 (58.1%) of 74 fetuses were miscarried, 2 were stillborn (2.7%), and 29 were liveborn (39.2%), including 11 at less than 37 weeks. Unencapsulated H. influenzae infection during the first 24 weeks was associated with fetal loss (44/47; 93.6%) and extremely premature birth (3/47; 6.4%). During the second half of pregnancy, unencapsulated H. influenzae infection in 28 cases was associated with premature birth and stillbirth in 8 (28.6%) and 2 (7.1%) cases, respectively. The incidence of pregnancy loss was 61.0 of 100 pregnancies for women with invasive disease and 60.8 of 100 for those with unencapsulated H. influenzae. Crude incidence rate ratios for pregnancy loss were 2.91 and 2.90 for all serotypes and unencapsulated H. influenzae, respectively. For suspected intrapartum sepsis, intrauterine death, septic abortion, or premature rupture of membranes, vaginal and placental samples should be tested for H. influenzae. A joint medical record for mothers and their infants would assist with developing evidence-based standards to reducing maternal and neonatal morbidity and mortality resulting from H. influenzae infection.No Full Tex

An explosive outbreak of Streptococcus pneumoniae serotype-8 infection in a highly vaccinated residential care home, England, Summer 2012

In August 2012, an explosive outbreak of severe lower respiratory tract infection (LRTI) due to Streptococcus pneumoniae serotype-8 occurred in a highly vaccinated elderly institutionalized population in England. Fifteen of 23 residents developed LRTI over 4 days (attack rate 65%); 11 had confirmed S. pneumoniae serotype-8 disease, and two died. Following amoxicillin chemoprophylaxis and pneumococcal polysaccharide vaccine (PPV) re-vaccination no further cases occurred in the following 2 months. No association was found between being an outbreak-associated case and age (P = 0·36), underlying comorbidities [relative risk (RR) 0·84 95% confidence interval (CI) 0·34–2·09], or prior receipt of PPV (RR 1·4, 95% CI 0·60–3·33). However, the median number of years since PPV was significantly higher for cases (n = 15, 10·2 years, range 7·3–17·9 years) than non-cases (n = 8, 7·2 years, range 6·8–12·8 years) (P = 0·045), provided evidence of waning immunity. Alternative vaccination strategies should be considered to prevent future S. pneumoniae outbreaks in institutionalized elderly populations.No Full Tex

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.Full Tex

<i>Haemophilus influenzae</i> type b reemergence after combination immunization

An increase in Haemophilus influenzae type b (Hib) in British children has been linked to the widespread use of a diphtheria/tetanus/acellular pertussis combination vaccine (DTaP-Hib). We measured anti-polyribosyl-ribitol phosphate antibody concentration and avidity before and after a Hib booster in 176 children 2-4 years of age who had received 3 doses of DTP-Hib (either DT whole cell pertussis-Hib or DTaP-Hib) combination vaccine in infancy. We also measured pharyngeal carriage of Hib. Antibody concentrations before and avidity indices after vaccination were low (geometric mean concentration 0.46 mug/mL, 95% confidence interval [CI] 0.36-0.58; geometric mean avidity index 0.16, 95% CI 0.14-0.18) and inversely related to the number of previous doses of DTaP-Hib (p = 0.02 and p<0.001, respectively). Hib was found in 2.1% (95% CI 0.7%-6.0%) of study participants. Our data support an association between DTaP-Hib vaccine combinations and clinical Hib disease through an effect on antibody concentration and avidity