RSV-related Community COPD Exacerbations and Novel Diagnostics: A Binational Prospective Cohort Study.

RATIONALE: Respiratory syncytial virus (RSV) is a common global respiratory virus increasingly recognized as a major pathogen in frail older adults and as a cause of chronic obstructive pulmonary disease (COPD) exacerbations. There is no single test for RSV in adults with acceptable diagnostic accuracy. Trials of RSV vaccines have recently shown excellent safety and efficacy against RSV in older adults; defining the frequency of RSV-related community infections and COPD exacerbations is important for vaccine deployment decisions. OBJECTIVES: This prospective study aimed to establish the frequency of outpatient-managed RSV-related exacerbations of COPD in two well-characterized patient cohorts using a combination of diagnostic methods. METHODS: Participants were recruited at specialist clinics in London, UK and Groningen, NL from 2017 and observed for three consecutive RSV seasons, during exacerbations and at least twice yearly. RSV infections were detected by reverse transcription-polymerase chain reaction (RT-PCR) and serologic testing. MEASUREMENTS AND MAIN RESULTS: 377 patients with COPD attended 1,999 clinic visits and reported 310 exacerbations. There were 27 RSV-related exacerbations (8·7% of total); of these, seven were detected only on PCR, 16 only on serology and 4 by both methods. Increases in RSV specific N-protein antibody were as sensitive as antibody to pre-F or post-F for serodiagnosis of RSV related exacerbations. CONCLUSIONS: RSV is associated with 8.7% of outpatient managed COPD exacerbations in this study. Antibodies to RSV-N protein may have diagnostic value, potentially important in a vaccinated population. The introduction of vaccines that prevent RSV is expected to benefit patients with COPD. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Nasopharyngeal Carriage of Pneumococcus in Children in England up to 10 Years After 13-Valent Pneumococcal Conjugate Vaccine Introduction: Persistence of Serotypes 3 and 19A and Emergence of 7C.

BACKGROUND: Monitoring changes in pharyngeal carriage of pneumococcus in children following 13-valent pneumococcal conjugate vaccine (PCV13) introduction in the United Kingdom in 2010 informs understanding of patterns of invasive pneumococcal disease (IPD) incidence. METHODS: Nasopharyngeal swabs from healthy children vaccinated with PCV13 according to schedule (2, 4, and 12 months) were cultured and serotyped. Results for children aged 13-48 months were compared between 2014-2015 and 2017-2019 and with children aged 6-12 months (2017-2020). Blood was obtained from a subset of children for pneumococcal serotype-specific immunoglobulin G (IgG). RESULTS: Total pneumococcal carriage at 13-48 months was 47.9% (473/988) in 2014-2015 and 51.8% (412/795) in 2017-2019 (P = .10); at age 6-12 months this value was 44.6% (274/615). In 2017-2019, 2.9% (95% confidence interval, 1.8%-4.3%) of children aged 13-48 months carried PCV13 serotypes (mainly 3 [1.5%] and 19A [0.8%]) and >20% carried the additional 20-valent PCV (PCV20) serotypes. Similar proportions of children had IgG ≥0.35 IU/mL for each serotype in 2014-2015 and 2017-2019. Serotype 7C carriage increased significantly (P < .01) between 2014-2015 and 2017-2019. Carriage of PCV20 serotypes 8 and 12F, both major causes of IPD, was rare. CONCLUSIONS: Introduction of PCV20, if licensed for children, could significantly change the composition of pneumococcal serotypes carried in the pharynx of UK children. CLINICAL TRIALS REGISTRATION: NCT03102840.

EULAR/PRES recommendations for vaccination of paediatric patients with autoimmune inflammatory rheumatic diseases: update 2021.

OBJECTIVES: Recent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying antirheumatic drugs in paediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) necessitated updating the EULAR recommendations. METHODS: Recommendations were developed using the EULAR standard operating procedures. Two international expert committees were formed to update the vaccination recommendations for both paediatric and adult patients with AIIRD. After a systematic literature review, separate recommendations were formulated for paediatric and adult patients. For pedAIIRD, six overarching principles and seven recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement. RESULTS: In general, the National Immunisation Programmes (NIP) should be followed and assessed yearly by the treating specialist. If possible, vaccinations should be administered prior to immunosuppressive drugs, but necessary treatment should never be postponed. Non-live vaccines can be safely given to immunosuppressed pedAIIRD patients. Mainly, seroprotection is preserved in patients receiving vaccinations on immunosuppression, except for high-dose glucocorticoids and B-cell depleting therapies. Live-attenuated vaccines should be avoided in immunosuppressed patients. However, it is safe to administer the measles-mumps-rubella booster and varicella zoster virus vaccine to immunosuppressed patients under specific conditions. In addition to the NIP, the non-live seasonal influenza vaccination should be strongly considered for immunosuppressed pedAIIRD patients. CONCLUSIONS: These recommendations are intended for paediatricians, paediatric rheumatologists, national immunisation agencies, general practitioners, patients and national rheumatology societies to attain safe and effective vaccination and optimal infection prevention in immunocompromised pedAIIRD patients.

Bordetella pertussis Induces Interferon Gamma Production by Natural Killer Cells, Resulting in Chemoattraction by Respiratory Epithelial Cells.

BACKGROUND: Whooping cough is caused by infection of the airways with Bordetella pertussis (Bp). As interferon gamma (IFN-γ) is essential for protective immunity against Bp, we investigated how IFN-γ is induced by Bp or the virulence antigens filamentous hemagglutinin adhesin, pertactin, or pertussis toxin, and how IFN-γ contributes to local immune responses in humans. METHODS: Peripheral blood mononuclear cells (PBMCs) from healthy donors and/or respiratory epithelial cells were stimulated with soluble antigens or inactivated intact Bp and the presence or absence of blocking antibodies or chemokines. Supernatants and cells were analyzed for IFN-γ and chemokine production, and lymphocyte migration was tested using epithelial supernatants. RESULTS: The soluble antigens failed to induce IFN-γ production, whereas inactivated Bp induced IFN-γ production. Natural killer (NK) cells were the main source of IFN-γ production, which was enhanced by interleukin 15. Epithelial-PBMC co-cultures showed robust IFN-γ-dependent CXCL9 and CXCL10 production by the epithelial cells following stimulation with IFN-γ and Bp. The epithelial-derived chemokines resulted in CXCR3-dependent recruitment of NK and T cells. CONCLUSIONS: Inactivated Bp, but not antigens, induced potent IFN-γ production by NK cells, resulting in chemoattraction of lymphocytes toward the respiratory epithelium. These data provide insight into the requirements for IFN-γ production and how IFN-γ enhances local immune responses to prevent Bp-mediated disease.

Recurrent Respiratory Syncytial Virus Infection in a CD14-Deficient Patient.

BACKGROUND: Recurrent respiratory syncytial virus (RSV) infection requiring hospitalization is rare and the underlying mechanism is unknown. We aimed to determine the role of CD14-mediated immunity in the pathogenesis of recurrent RSV infection. METHODS: We performed genotyping and longitudinal immunophenotyping of the first patient with a genetic CD14 deficiency who developed recurrent RSV infection. We analyzed gene expression profiles and interleukin (IL)-6 production by patient peripheral blood mononuclear cells in response to RSV pre- and post-fusion (F) protein. We generated CD14-deficient human nasal epithelial cells cultured at air-liquid interface (HNEC-ALI) of patient-derived cells and after CRISPR-based gene editing of control cells. We analyzed viral replication upon RSV infection. RESULTS: Sanger sequencing revealed a homozygous single-nucleotide deletion in CD14, resulting in absence of the CD14 protein in the index patient. In vitro, viral replication was similar in wild-type and CD14-/- HNEC-ALI. Loss of immune cell CD14 led to impaired cytokine and chemokine responses to RSV pre- and post-F protein, characterized by absence of IL-6 production. CONCLUSIONS: We report an association of recurrent RSV bronchiolitis with a loss of CD14 function in immune cells. Lack of CD14 function led to defective immune responses to RSV pre- and post-F protein without a change in viral replication.

Vaccine Impact and Effectiveness of Meningococcal Serogroup ACWY Conjugate Vaccine Implementation in the Netherlands: A Nationwide Surveillance Study.

BACKGROUND: In response to the recent serogroup W invasive meningococcal disease (IMD-W) epidemic in the Netherlands, meningococcal serogroup C (MenC) conjugate vaccination for children aged 14 months was replaced with a MenACWY conjugate vaccination, and a mass campaign targeting individuals aged 14-18 years was executed. We investigated the impact of MenACWY vaccination implementation in 2018-2020 on incidence rates and estimated vaccine effectiveness (VE). METHODS: We extracted IMD cases diagnosed between July 2014 and December 2020 from the national surveillance system. We calculated age group-specific incidence rate ratios by comparing incidence rates before (July 2017-March 2018) and after (July 2019-March 2020) MenACWY vaccination implementation. We estimated VE in vaccine-eligible cases using the screening method. RESULTS: Overall, the IMD-W incidence rate declined by 61% (95% confidence interval [CI], 40 to 74). It declined by 82% (95% CI, 18 to 96) in the vaccine-eligible age group (individuals aged 15-36 months and 14-18 years) and by 57% (95% CI, 34 to 72) in vaccine-noneligible age groups. VE was 92% (95% CI, -20 to 99.5) in vaccine-eligible toddlers (aged 15-36 months). No IMD-W cases were reported in vaccine-eligible teenagers after the campaign. CONCLUSIONS: The MenACWY vaccination program was effective in preventing IMD-W in the target population. The IMD-W incidence reduction in vaccine-noneligible age groups may be caused by indirect effects of the vaccination program. However, disentangling natural fluctuation from vaccine effect was not possible. Our findings encourage the use of toddler and teenager MenACWY vaccination in national immunization programs.

Antibody Responses to Respiratory Syncytial Virus: A Cross-Sectional Serosurveillance Study in the Dutch Population Focusing on Infants Younger Than 2 Years.

BACKGROUND: Respiratory syncytial virus (RSV) generally causes mild disease but can cause severe infections in (premature) infants and elderly adults. Here, we studied RSV-specific antibody concentrations throughout life with emphasis on infants and chronic obstructive pulmonary disease (COPD) patients. METHODS: Sera (N = 2655) from 2 nationwide cross-sectional studies in the Netherlands including individuals aged 0-90 years were analyzed for IgG and IgA antibodies to RSV prefusion F, postfusion F, N, Ga, and Gb proteins and for antibody avidity in 42 COPD patients. RESULTS: Maternal IgG concentrations declined to age 10-12 months. After the first year of life, approximately 40% of children lacked infection-induced IgA antibodies and may therefore be uninfected. All Dutch children showed serological evidence of RSV infection by age 3 years. Antibody concentrations reached a plateau by age 5-9 years and remains constant throughout life. COPD patients had similar levels and avidity of RSV-specific IgG antibodies compared with age-matched healthy controls. CONCLUSIONS: RSV-IgG antibody patterns throughout life can be used to estimate the degree of immunity acquisition to RSV and to identify groups at increased risk of infection. Seroprevalence of IgA could be a proxy to determine RSV infection in children younger than 1 year.

Nasopharyngeal Microbiota Profiles in Rural Venezuelan Children Are Associated With Respiratory and Gastrointestinal Infections.

BACKGROUND: Recent research suggests that the microbiota affects susceptibility to both respiratory tract infections (RTIs) and gastrointestinal infections (GIIs). In order to optimize global treatment options, it is important to characterize microbiota profiles across different niches and geographic/socioeconomic areas where RTI and GII prevalences are high. METHODS: We performed 16S sequencing of nasopharyngeal swabs from 209 Venezuelan Amerindian children aged 6 weeks-59 months who were participating in a 13-valent pneumococcal conjugate vaccine (PCV13) study. Using random forest models, differential abundance testing, and regression analysis, we determined whether specific bacteria were associated with RTIs or GIIs and variation in PCV13 response. RESULTS: Microbiota compositions differed between children with or without RTIs (P = .018) or GIIs (P = .001). Several species were associated with the absence of infections. Some of these health-associated bacteria are also observed in developed regions, such as Corynebacterium (log2(fold change [FC]) = 3.30 for RTIs and log2(FC) = 1.71 for GIIs), while others are not commonly observed in developed regions, such as Acinetobacter (log2(FC) = 2.82 and log2(FC) = 5.06, respectively). Klebsiella spp. presence was associated with both RTIs (log2(FC) = 5.48) and GIIs (log2(FC) = 7.20). CONCLUSIONS: The nasopharyngeal microbiota of rural Venezuelan children included several bacteria that thrive in tropical humid climates. Interestingly, nasopharyngeal microbiota composition not only differed in children with an RTI but also in those with a GII, which suggests a reciprocal interplay between the 2 environments. Knowledge of region-specific microbiota patterns enables tailoring of preventive and therapeutic approaches.

Respiratory syncytial virus in young children: community cohort study integrating serological surveys, questionnaire and electronic health records, Born in Bradford cohort, England, 2008 to 2013.

BackgroundBronchiolitis caused by respiratory syncytial virus (RSV) is a major cause of mortality and morbidity in infants.AimTo describe RSV epidemiology in children in the community in a high-income setting.MethodsWe used stored blood samples from the United Kingdom Born in Bradford cohort study that had been collected at birth, age 1 and 2 years old, tested for IgG RSV postfusion F antibody and linked to questionnaires and primary and hospital care records. We used finite mixture models to classify children as RSV infected/not infected according to their antibody concentrations at age 1 and 2 years. We assessed risk factors for primary RSV infection at each age using Poisson regression models.ResultsThe study cohort included 700 children with cord blood samples; 490 had additional blood samples taken at both ages 1 and 2 years old. Of these 490 children, 258 (53%; 95% confidence interval (CI): 48-57%) were first infected with RSV at age 1, 99 of whom (38%; 95% CI: 33-43%) had been in contact with healthcare during peak RSV season (November-January). Having older siblings, birth in October-June and attending formal childcare were associated with risk of RSV infection in infancy. By age 2, a further 164 of 490 children (33%; 95% CI: 29-38%) had been infected.ConclusionOver half of children experienced RSV infection in infancy, a further one third had evidence of primary RSV infection by age 2, and one in seven remained seronegative by their second birthday. These findings will inform future analyses to assess the cost-effectiveness of RSV vaccination programmes in high-income settings.

Persistent Circulation of Vaccine Serotypes and Serotype Replacement After 5 Years of Infant Immunization With 13-Valent Pneumococcal Conjugate Vaccine in the United Kingdom.

BACKGROUND: Following programmatic introduction of the 13-valent pneumococcal conjugate vaccine (PCV13), there is residual carriage and disease due to PCV13-covered serotypes. METHODS: PCV13-immunized children aged 13-48 months, N = 988, were enrolled between February 2014 and August 2015 ("late PCV13"), and had nasopharyngeal pneumococcal carriage compared with 7-valent pneumococcal conjugate vaccine (PCV7) immunized children, N = 567, enrolled between November 2010 and September 2011 ("early PCV13"). Nasopharyngeal pneumococci were molecular-serotyped by microarray. Invasive pneumococcal disease (IPD) cases were identified through enhanced national surveillance. RESULTS: Compared with PCV7-immunized children, carriage among PCV13-immunized children was significantly lower for serotypes 19A (odds ratio [OR], 0.08 [95% confidence interval {CI}, .02-.25]), 6C (OR, 0.11 [95% CI, .03-.32]), and 7F (8 vs 0 cases). IPD incidence in children <5 years was significantly lower for serotypes 1 (incidence rate ratio [IRR], 0.03 [95% CI, 0-.19]) and 7F (IRR, 0.13 [95% CI, .05-.36]) but not 19A (IRR, 0.6 [95% CI, .3-1.12]) or serotype 3 (IRR, 2.3 [95% CI, .86-6.15]) in the late PCV13 period than in the early PCV13 period. The most significant rises in IPD incidence were for serotypes 8, 12F, and 24F. CONCLUSIONS: PCV13 has reduced serotype 19A carriage among vaccinated children. We found no impact of PCV13 on serotype 3 carriage or disease, and emergence of non-PCV13-serotype disease.

Controlled Human Infection With Bordetella pertussis Induces Asymptomatic, Immunizing Colonization.

BACKGROUND: Bordetella pertussis is among the leading causes of vaccine-preventable deaths and morbidity globally. Human asymptomatic carriage as a reservoir for community transmission of infections might be a target of future vaccine strategies, but has not been demonstrated. Our objective was to demonstrate that asymptomatic nasopharyngeal carriage of Bordetella pertussis is inducible in humans and to define the microbiological and immunological features of presymptomatic infection. METHODS: Healthy subjects aged 18-45 years with an antipertussis toxin immunoglobin G (IgG) concentration of <20 international units/ml were inoculated intranasally with nonattenuated, wild-type Bordetella pertussis strain B1917. Safety, colonization, and shedding were monitored over 17 days in an inpatient facility. Colonization was assessed by culture and quantitative polymerase chain reaction. Azithromycin was administered from Day 14. The inoculum dose was escalated, aiming to colonize at least 70% of participants. Immunological responses were measured. RESULTS: There were 34 participants challenged, in groups of 4 or 5. The dose was gradually escalated from 103 colony-forming units (0% colonized) to 105 colony-forming units (80% colonized). Minor symptoms were reported in a minority of participants. Azithromycin eradicated colonization in 48 hours in 88% of colonized individuals. Antipertussis toxin IgG seroconversion occurred in 9 out of 19 colonized participants and in none of the participants who were not colonized. Nasal wash was a more sensitive method to detect colonization than pernasal swabs. No shedding of Bordetella pertussis was detected in systematically collected environmental samples. CONCLUSIONS: Bordetella pertussis colonization can be deliberately induced and leads to a systemic immune response without causing pertussis symptoms. CLINICAL TRIALS REGISTRATION: NCT03751514.

Association of Routine Infant Vaccinations With Antibody Levels Among Preterm Infants.

Importance: The standard schedule of national immunization programs for infants may not be sufficient to protect extremely and very preterm infants. Objective: To evaluate the immunogenicity of routine vaccinations administered to preterm infants. Design, Setting, and Participants: A multicenter, prospective, observational cohort study of preterm infants stratified according to gestational age recruited from 8 hospitals across the Netherlands between October 2015 and October 2017, with follow-up until 12 months of age (October 2018). In total, 296 premature infants were enrolled and compared with a control group of 66 healthy term infants from a 2011 study, immunized according to the same schedule with the same vaccines. Exposures: Three primary doses of the diphtheria-tetanus toxoids-acellular pertussis-inactivated poliomyelitis-Haemophilus influenza type b-hepatitis B combination vaccine were given at 2, 3, and 4 months after birth followed by a booster at 11 months and a 10-valent pneumococcal conjugate vaccine at 2, 4, and 11 months after birth. Main Outcomes and Measures: Primary end points were (1) proportion of preterm infants who achieved IgG antibody against vaccine antigens at concentrations above the internationally defined threshold for protection after the primary series and booster dose and (2) serum IgG geometric mean concentrations after the primary series and booster vaccination. Proportions and geometric mean concentrations were compared in preterm infants and the control group of term infants. Results: Of 296 preterm infants (56.1% male; mean gestational age, 30 weeks), complete samples before vaccination, 1 month after the primary series, and 1 month after the booster were obtained from 220 preterm infants (74.3%). After the primary series, the proportion of preterm infants across all gestational age groups who achieved protective IgG antibody levels against pertussis toxin, diphtheria, tetanus and 6 of 10 pneumococcal serotypes varied between 83.0% and 100%, Haemophilus influenzae type b between 34.7% and 46.2% (40.6% among all preterm infants overall), and pneumococcal serotypes 4, 6B, 18C, and 23F between 45.8% and 75.1%. After the booster dose, protective antibody levels were achieved in more than 95% of all preterm groups, except for Haemophilus influenzae type b (88.1%). In general, geometric mean concentrations of all vaccine-induced antibodies were significantly lower in all preterm infants vs term infants, except for pertussis toxin and pneumococcal serotypes 4 and 19F after the primary series and booster vaccination. Conclusions and Relevance: Among preterm infants, administration of routine vaccinations during the first year of life was associated with protective antibody levels against most antigens in the majority of infants after the primary series and booster, except for Haemophilus influenzae type b. However, antibody concentrations were generally lower among preterm infants compared with historical controls.

Use of saliva to monitor meningococcal vaccine responses: proposing a threshold in saliva as surrogate of protection.

BACKGROUND: Mucosal antibodies against capsular polysaccharides offer protection against acquisition and carriage of encapsulated bacteria like Neisseria meningitidis serogroup C. Measurements of salivary antibodies as replacement for blood testing has important (cost-effective) advantages, particular in studies that assess the impact of large-scale vaccination or in populations in which blood sampling is difficult. This study aimed to estimate a threshold for meningococcal IgG salivary antibody levels to discriminate between unprotected and protected vaccinated individuals. METHODS: MenA-, MenC-, MenW- and MenY-polysaccharide (PS) specific IgG levels in serum and saliva from participants in a meningococcal vaccination study were measured using the fluorescent-bead-based multiplex immunoassay. Functional antibody titers in serum against the four serogroups were measured with serum bactericidal assay using rabbit complement (rSBA). A threshold for salivary IgG was determined by analysis of ROC curves using a serum rSBA titer ≥128 as correlate of protection. The area under the curve (AUC) was calculated to quantify the accuracy of the salivary test and was considered adequate when ≥0.80. The optimal cut-off was considered adequate when salivary IgG cut-off levels provided specificity of ≥90%. True positive rate (sensitivity), positive predictive value, and negative predictive value were calculated to explore the possible use of salivary antibody levels as a surrogate of protection. RESULTS: The best ROC curve (AUC of 0.95) was obtained for MenC, with an estimated minimum threshold of MenC-PS specific salivary IgG ≥3.54 ng/mL as surrogate of protection. An adequate AUC (> 0.80) was also observed for MenW and MenY with an estimated minimal threshold of 2.00 and 1.82 ng/mL, respectively. When applying these thresholds, all (100%) samples collected 1 month and 1 year after the (booster) meningococcal vaccination, that were defined as protective in the saliva test for MenC, MenW and MenY, corresponded with concomitant serum rSBA titer ≥128 for the respective meningococcal serogroups. CONCLUSION: The saliva test offers an alternative screening tool to monitor protective vaccine responses up to one year after meningococcal vaccination against MenC, MenW and MenY. Future (large) longitudinal vaccination studies evaluating also clinical protection against IMD or carriage acquisition are required to validate the currently proposed threshold in saliva.

Opsonic Phagocytosis in Chronic Obstructive Pulmonary Disease Is Enhanced by Nrf2 Agonists.

RATIONALE: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AMs) in patients with chronic obstructive pulmonary disease (COPD), but the mechanisms and clinical consequences remain incompletely defined. OBJECTIVES: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences, and potential for therapeutic manipulation of these defects. METHODS: We isolated AMs and monocyte-derived macrophages (MDMs) from a cohort of patients with COPD and control subjects within the Medical Research Council COPDMAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features. MEASUREMENTS AND MAIN RESULTS: COPD AMs and MDMs have impaired phagocytosis of Streptococcus pneumoniae. COPD AMs have a selective defect in uptake of opsonized bacteria, despite the presence of antipneumococcal antibodies in BAL, not observed in MDMs or healthy donor AMs. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria, and health-related quality-of-life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AMs was not reduced. COPD AMs have reduced transcriptional responses to opsonized bacteria, such as cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2 (nuclear factor erythroid 2-related factor 2)-regulated genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and compound 7) reverse defects in phagocytosis of S. pneumoniae and nontypeable Haemophilus influenzae by COPD AMs. CONCLUSIONS: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AMs, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.

Pertactin-deficient Bordetella pertussis isolates: evidence of increased circulation in Europe, 1998 to 2015.

IntroductionPertussis outbreaks have occurred in several industrialised countries using acellular pertussis vaccines (ACVs) since the 1990s. High prevalence of pertactin (PRN)-deficient Bordetella pertussis isolates has been found in these countries.AimsTo evaluate in Europe: (i) whether proportions of PRN-deficient strains increased in consecutive collections of B. pertussis clinical isolates; (ii) if the frequency of PRN-deficient strains in countries correlated with the time since ACV introduction; (iii) the presence of pertussis toxin (PT)-, filamentous haemagglutinin (FHA)- or fimbriae (Fim)-deficient isolates.MethodsB. pertussis clinical isolates were obtained from different European countries during four periods (EUpert I-IV studies): 1998 to 2001 (n = 102), 2004 to 2005 (n = 154), 2007 to 2009 (n = 140) and 2012 to 2015 (n = 265). The isolates' selection criteria remained unchanged in all periods. PRN, PT, FHA and Fim2 and Fim3 expression were assessed by ELISA.ResultsIn each period 1.0% (1/102), 1.9% (3/154), 6.4% (9/140) and 24.9% (66/265) of isolates were PRN-deficient. In EUpert IV, PRN-deficient isolates occurred in all countries sampled and in six countries their frequency was higher than in EUpert III (for Sweden and the United Kingdom, p < 0.0001 and p = 0.0155, respectively). Sweden and Italy which used ACVs since the mid 1990s had the highest frequencies (69%; 20/29 and 55%; 11/20, respectively) while Finland, where primary immunisations with ACV containing PRN dated from 2009 had the lowest (3.6%). Throughout the study, no PT- or FHA-deficient isolate and one Fim2/3-deficient was detected.ConclusionResults suggest that the longer the period since the introduction of ACVs containing PRN, the higher the frequency of circulating PRN-deficient isolates.

Surveillance of Circulating Bordetella pertussis Strains in Europe during 1998 to 2015.

One reason for increased pertussis incidence is the adaptation of Bordetella pertussis to vaccine-induced immunity by modulating its genomic structure. This study, EUpert IV, includes 265 isolates collected from nine European countries during 2012 to 2015 (n = 265) and compares the results to previous EUpert I to III studies (1998 to 2009). The analyses included genotyping, serotyping, pulsed-field gel electrophoresis (PFGE), and multilocus variable-number tandem-repeat analysis (MLVA). Genotyping results showed only small variations among the common virulence genes of B. pertussis The frequencies of serotypes Fim2 and Fim3 varied among the four collections. Genomic analyses showed that MLVA type 27 increased to 80% between the periods of 1998 to 2001 and 2012 to 2015. Two PFGE profiles, BpSR3 (29.4%) and BpSR10 (27.2%), constituted more than 50% of the circulating isolates in the present collection. Our study indicates that the European B. pertussis population is changing and became more homogenous after the introduction of acellular pertussis vaccines.

Dutch national immunization schedule: compliance and associated characteristics for the primary series.

In the Netherlands, the recommended priming immunization schedule for diphtheria, tetanus, pertussis and polio (DTaP-IPV) is at 2, 3 and 4 months of age. We evaluated the compliance with the recommended schedule, as well as its characteristics. We included all infants born between 2007 and 2012 who received minimally one DTaP-IPV vaccination (n = 1,061,578). Infants complied with the schedule if they received the first vaccination between 6 and 9 weeks of age, and the second and third vaccination 2-6 weeks after the first and second vaccination. We examined associations between compliance and several characteristics using log-binomial regression. Compliance for the first, second and third vaccination was 81.6, 88.3 and 84.2%, respectively. Compliance with the total recommended schedule was 64.5%, and increased from 60.1% for 2007 to 68.5% for 2012. Compliance was higher for full-term infants (65.9%), infants with normal birth weight (66.0%) and when both parents were born in the Netherlands (66.8%). CONCLUSION: Delayed vaccination during the primary vaccination schedule occurs in one sixth of the Dutch children. Efforts to improve compliance should be focused in particular on preterm infants, infants with low birth weight and infants whose parents are not born in the Netherlands. What is Known: • A delayed start of vaccination leads to a longer period at risk for infectious diseases, e.g. pertussis • Delayed vaccination is associated with several factors including prematurity, low birth weight, family size, birth order, low socioeconomic status and health status of the child What is New: • Compliance with the recommended priming immunization schedule for diphtheria, tetanus, pertussis and polio was 64.5%, and increased from 60.1% for 2007 to 68.5% for 2012 • If the first vaccination was delayed, there was a higher chance that the following vaccinations were administered 'out-of-schedule' as well, resulting in even a higher age at second and third vaccination.

Enhanced Bordetella pertussis acquisition rate in adolescents during the 2012 epidemic in the Netherlands and evidence for prolonged antibody persistence after infection.

IntroductionIn 2012 a large epidemic of pertussis occurred in the Netherlands. We assessed pertussis toxin (PT) antibody levels in longitudinal serum samples from Dutch 10-18 year-olds, encompassing the epidemic, to investigate pertussis infection incidence. Methods: Blood was sampled in October 2011 (n = 239 adolescents), then 1 year (2012; n = 228) and 3 years (2014; n = 167) later. PT-IgG concentrations were measured by immunoassay and concentrations ≥50 IU/mL (seropositive) assumed indicative of an infection within the preceding year. Results: During the 2012 epidemic, 10% of participants became seropositive, while this was just 3% after the epidemic. The pertussis acquisition rate proved to be sixfold higher during the epidemic (97 per 1,000 person-years) compared with 2012-2014 (16 per 1,000 person-years). In 2012, pertussis notifications among adolescents nationwide were 228/100,000 (0.23%), which is at least 40 times lower than the seropositivity percentage. Remarkably, 17 of the 22 seropositive participants in 2011, were still seropositive in 2012 and nine remained seropositive for at least 3 years. Discussion: Longitudinal studies allow a better estimation of pertussis infections in the population. A PT-IgG concentration ≥50 IU/mL as indication of recent infection may overestimate these numbers in cross-sectional serosurveillance and should be used carefully.

Disease Burden of Invasive Meningococcal Disease in the Netherlands Between June 1999 and June 2011: A Subjective Role for Serogroup and Clonal Complex.

BACKGROUND: Several countries consider the implementation of a meningococcal serogroup B vaccine for young children and/or serogroup C or ACWY conjugate vaccine for adolescents. Representative information on clinical course of invasive meningococcal disease (IMD) is useful to evaluate cost-effectiveness of vaccination. Information on the relation between infecting meningococcal clonal complex (CC), disease course and outcome of IMD is scarce. METHODS: A retrospective study using Dutch surveillance data on IMD from June 1999 to June 2011. Clinical information was retrieved from hospital records. The effect of age, comorbidity, clinical manifestation, serogroup, and CC on disease course and outcome was assessed in multivariable analyses. Meningococcal CCs were assessed by multilocus sequence typing. RESULTS: Clinical information was retrieved for 879 IMD cases: 48% of patients presented with meningitis, 17% with septic shock, and 22% with septic shock plus meningitis. Development of septic shock was not related to CC or serogroup. Median (interquartile range) duration of hospital admission was 10 (8-13) days. Intensive care unit admittance (38%) was higher for patients aged ≥10 years and patients with septic shock (P-values ≤.001). Case-fatality rate (8%) and development of sequelae (29%) was dependent on age and clinical manifestation (P-values ≤.001) and not affected by comorbidity, CC, or serogroup. CONCLUSIONS: IMD still coincides with a considerable disease burden and mortality. Disease course and outcome depend mainly on age and clinical manifestation and less on meningococcal CC or serogroup.

Differential B-cell memory around the 11-month booster in children vaccinated with a 10- or 13-valent pneumococcal conjugate vaccine.

BACKGROUND: Both the 10- and 13-valent pneumococcal conjugate vaccines (PCV10 and PCV13) induce immunological memory against Streptococcus pneumoniae infections caused by vaccine serotypes. In addition to comparing serum antibody levels, we investigated frequencies of serotype-specific plasma cells (PCs) and memory B-cells (Bmems) as potential predictors of long-term immunity around the booster vaccination at 11 months of age. METHODS: Infants were immunized with PCV10 or PCV13 at 2, 3, 4, and 11 months of age. Blood was collected before the 11-month booster or 7-9 days afterward. Serotype-specific immunoglobulin G (IgG) levels were determined in serum samples by multiplex immunoassay. Circulating specific PCs and Bmems against shared serotypes 1, 6B, 7F, and 19F and against PCV13 serotypes 6A and 19A were measured in peripheral blood mononuclear cells by enzyme-linked immunospot assay. RESULTS: No major differences in IgG levels and PC frequencies between groups were found for the 4 shared serotypes. Notably, PCV13 vaccination resulted in higher frequencies of Bmems than PCV10 vaccination, both before and after the booster dose, for all 4 shared serotypes except for serotype 1 postbooster. For PCV13-specific serotypes 6A and 19A, the IgG levels and frequencies of PCs and Bmems were higher in the PCV13 group, pre- and postbooster, except for PC frequencies prebooster. CONCLUSIONS: Both PCVs are immunogenic and induce measurable IgG, PC, and Bmem booster responses at 11 months. Compared to PCV10, vaccination with PCV13 was associated with overall similar IgG levels and PC frequencies but with higher Bmem frequencies before and after the 11-month booster. The clinical implications of these results need further follow-up. CLINICAL TRIALS REGISTRATION: NTR3069.