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Since 2009/10, a 10- and a 13-valent pneumococcal conjugate vaccine (PCV) are available, but only the 10-valent vaccine is now being used for the children in the Netherlands. As the vaccines differ in number of serotypes, antigen concentration, and carrier proteins this study was designed to directly compare quantity and quality of the antibody responses induced by PCV10 and PCV13 before and after the 11-month booster. Dutch infants (n = 132) were immunized with either PCV10 or PCV13 and DTaP-IPV-Hib-HepB at the age of 2, 3, 4 and 11 months. Blood samples were collected pre-booster and post-booster at one week and one month post-booster for quantitative and qualitative immunogenicity against 13 pneumococcal serotypes, as well as quantitative immunogenicity against diphtheria, tetanus, pertussis and Haemophilus influenzae type b. We compared immunogenicity induced by PCV13 and PCV10 for their ten shared serotypes. One month post-booster, pneumococcal serotype-specific IgG geometric mean concentrations (GMCs) for the PCV13 group were higher compared with the PCV10 group for six serotypes, although avidity was lower. Serotype 19F showed the most distinct difference in IgG and, in contrast to other serotypes, its avidity was higher in the PCV13 group. One week post-booster, opsonophagocytosis for serotype 19F did not differ significantly between the PCV10- and the PCV13 group. Both PCV10 and PCV13 were immunogenic and induced a booster response. Compared to the PCV10 group, the PCV13 group showed higher levels for serotype 19F GMCs and avidity, pre- as well as post-booster, although opsonophagocytosis did not differ significantly between groups. In our study, avidity is not correlated to opsonophagocytotic activity (OPA) and correlations between IgG and OPA differ per serotype. Therefore, besides assays to determine IgG GMCs, assays to detect opsonophagocytotic activity, i.e., the actual killing of the pneumococcus, are important for PCV evaluation. How differences between the two vaccines relate to long-term protection requires further investigation. www.trialregister.nl NTR3069.

•The study vaccine (Hib-TT) administered according to a 3+1 schedule is immunogenic.•Immune responses to Hib-TT vaccination and to licensed Hib vaccines are comparable.•Hib-TT primary and booster vaccination safety profiles are similar to other Hib vaccines.•Immune response to routine vaccines is not impacted by co-administration with Hib-TT. Vaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination. This phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6months (primary vaccination) and 15–18months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study. Of 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines’ antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5–96.7% and 99.6–100% of participants achieved anti-PRP levels ≥0.15µg/mL, while 78.3–89.8% and 97.9–99.1% had anti-PRP levels ≥1µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related. Hib-TT induced seroprotective antibody concentrations in the majority of participants and was well-tolerated when co-administered with routine pediatric vaccines according to a 3+1 schedule.

In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes. Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009-2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010-2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5-7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010. From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years. This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.

•An active surveillance through a phased introduction of the Hib vaccine in Japan was studied.•Hib disease incidence decreased significantly after vaccine introduction.•Hif and non-typeable H. influenzae were isolated from a few cases.•Serotype replacement was not observed after the introduction of the Hib vaccine.•Continuous capsular typing and strain identification surveillance is important. Haemophilus influenzae type b (Hib) vaccine was introduced as a voluntary vaccine in December 2008 and was included in the national routine immunization program in April 2013 in Japan. Currently, no nationwide data are available to evaluate the effectiveness of Hib vaccine in Japan. To evaluate the effectiveness of Hib vaccine in Japan, nationwide active population-based surveillance of culture-proven invasive infections caused by H. influenzae in children was performed in 2008–2017 in 10 prefectures in Japan (covering approximately 23% of the total Japanese population). Clinical data were recorded on a standardized case report form. Capsular type and antimicrobial susceptibility of the H. influenzae isolates were examined. The incidence rate ratio (IRR) and its confidence interval (CI) were calculated to compare data from 5 years before and that from after the introduction of the national routine Hib vaccine immunization program. During the 10-year study period, 566 invasive H. influenzae disease cases including 336 meningitis cases were identified. The average number of invasive H. influenzae disease cases among children <5 years of age during 2013–2017 decreased by 93% (IRR: 0.07, 95%CI 0.05–0.10, p < 0.001) compared with those occurring during 2008–2012. Hib strains have not been isolated from invasive H. influenzae disease cases since 2014; however, non-typeable H. influenzae and H. influenzae type f isolates have been noted as causes of invasive H. influenzae diseases among children <5 years in the post-Hib vaccine era. After the governmental subsidization of the Hib vaccine, invasive Hib disease cases decreased dramatically in the study population, as per our surveillance. Continuous surveillance is necessary to monitor the effectiveness of Hib vaccine and for detecting any emerging invasive capsular types.

Lack of rapid and comprehensive microbiological diagnosis in patients with community acquired pneumonia (CAP) hampers appropriate antimicrobial therapy. This study evaluates the real-world performance of the BioFire FilmArray Pneumonia panel plus (FAP plus ) and explores the feasibility of evaluation in a randomised controlled trial. Patients presenting to hospital with suspected CAP were recruited in a prospective feasibility study. An induced sputum or an endotracheal aspirate was obtained from all participants. The FAP plus turnaround time (TAT) and microbiological yield were compared with standard diagnostic methods (SDs). 96/104 (92%) enrolled patients had a respiratory tract infection (RTI); 72 CAP and 24 other RTIs. Median TAT was shorter for the FAP plus , compared with in-house PCR (2.6 vs 24.1 h, p < 0.001) and sputum cultures (2.6 vs 57.5 h, p < 0.001). The total microbiological yield by the FAP plus was higher compared to SDs (91% (162/179) vs 55% (99/179), p < 0.0001). Haemophilus influenzae , Streptococcus pneumoniae and influenza A virus were the most frequent pathogens. In conclusion, molecular panel testing in adults with CAP was associated with a significant reduction in time to actionable results and increased microbiological yield. The impact on antibiotic use and patient outcome should be assessed in randomised controlled trials.

Haemophilus influenzae, particularly H influenzae serotype b (Hib), is an important pathogen that causes serious diseases like meningitis and septicaemia. Since the introduction of Hib conjugate vaccines in the 1990s, the epidemiology of invasive H influenzae disease has changed substantially, with most infections now caused by non-Hib strains. We discuss the importance of H influenzae serotype a (Hia) as a cause of serious morbidity and mortality and its global epidemiology, clinical presentation, microbiology, immunology, prevention, and control. Much like Hib, the capsule of Hia is an important virulence factor contributing to the development of invasive disease. Molecular typing of Hia has identified distinct clonal groups, with some linked to severe disease and high case-fatality rates. Similarities between Hia and Hib capsules, their clinical presentation, and immunology of infection suggest that a bivalent Hia–Hib capsular polysaccharide-protein conjugate vaccine could offer protection against these two important serotypes of H influenzae.

Haemophilus influenzae reference laboratory from Portugal characterized the entire collection of 260 H. influenzae invasive isolates received between 2011 and 2018, with the purpose of updating the last published data (2002–2010). Capsular serotypes and antimicrobial susceptibility patterns were determined. The ftsI gene encoding the transpeptidase domain of PBP3 was sequenced for β-lactamase-negative ampicillin-resistant (BLNAR) isolates. Multilocus sequence typing (MLST) was performed to examine genetic relatedness among isolates. The majority of H. influenzae invasive isolates are nonencapsulated (NTHi-79.2%). Among encapsulated isolates (20.8%), the most characterized serotype was serotype b (13.5%), followed by serotype f (3.1%), serotype a (2.7%), and serotype e (1.5%). In contrast to NTHi that mainly affected the elderly (64.0%; ≥ 65 years old), most encapsulated isolates were characterized in preschool children (55.6%). Comparing the two periods, β-lactamase production increased from 10.4 to 13.5% (p = 0.032) and low-BLNAR (MIC ≥ 1 mg/L) isolates from 7.7 to 10.5% (p = 0.017). NTHi showed high genetic diversity (60.7%), in opposition to encapsulated isolates that were clonal within each serotype. Interestingly, ST103 and ST57 were the predominant STs among NTHi, with ST103 being associated with β-lactamase-producers and ST57 with non-β-lactamase-producers. In Portugal, susceptible and genetically diverse NTHi H. influenzae continues to be responsible for invasive disease, mainly in the elderly. Nevertheless, we are now concerned with Hib circulating in children we believe to have been vaccinated. Our data reiterates the need for continued surveillance, which will be useful in the development of public health prevention strategies.

Haemophilus influenzae type b (Hib) conjugate vaccines have drastically reduced disease incidence worldwide. Protection against Hib infection has relied on the serum bactericidal activity (SBA) of antibodies to the Hib capsular polysaccharide (polyribosylribitol phosphate). However, licensure usually relies on measuring induction of antibodies to PRP as a surrogate for SBA. In a phase III clinical trial we compared a PRP-conjugate vaccine using the nontoxic diphtheria toxin mutant, CRM197, as carrier protein with the licensed tetanus toxoid conjugate when administered subcutaneously as a three dose primary series in Japanese infants. As an addition to the phase III study, we have now evaluated SBA and show PRP-CRM197 induces higher levels of SBA than PRP-T four weeks after the primary series, with a statistically significant correlation with anti-PRP titers. This data confirms the superior immunogenicity of PRP-CRM197 compared with PRP-T assessed as SBA following a three-dose primary series by subcutaneous administration. Clinical trial registry: Registered on ClinicalTrials.gov (NCT01379846).

Vaccination is considered as the most cost effective method for preventing infectious diseases. Low grade fever is a known adverse effect of vaccination. In India, it is a common clinical practice to prescribe paracetamol either prophylactically or therapeutically to manage fever. Some studies have shown that paracetamol interferes with antibody responses following immunization. This manuscript reports the outcome of a post hoc analysis of data from a clinical trial of a pentavalent vaccine in Indian infants where paracetamol was not used or was used either as prophylaxis or for treatment of fever. Pre and post vaccine antibody levels against Diphtheria, Tetanus, Pertussis, Hepatitis B, Haemophilus influenzae type B were assessed in no paracetamol and paracetamol groups. The paracetamol group was further divided into prophylactic and treatment groups. Similar rates of seroprotection/seroresponse for anti-D, anti-T, anti-wP, anti-PT, anti-HBs and anti-PRP were observed in all the groups. There was no clear tendency for difference in percentage seroprotection/seroresponse and geometric mean (GM) titers in any of the groups. The study found no evidence that paracetamol usage either as prophylactic or for treatment impact immunological responses to DTwP-HepB-Hib combination vaccine. [Clinical trial registry of India (study registration number CTRI/2012/08/002872)].

Development of vaccines to prevent disease and death from , and nontypeable (NTHi), the main pathogens that cause otitis media, pneumonia, meningitis and sepsis, are a global priority. Children living in low and lower-middle income settings are at the highest risk of contracting and dying from these diseases. Improved vaccines with broader coverage are required. Data on the natural development of antibodies to putative vaccine antigens, especially in high-risk settings, can inform the rational selection of the best antigens for vaccine development. Serum IgG titres to four pneumococcal proteins (PspA1, PspA2, CbpA, and Ply) and five NTHi antigens (P4, P6, OMP26, rsPilA and ChimV4) were measured in sera collected from 101 Papua New Guinean children at 1, 4, 9, 10, 23 and 24 months of age using multiplexed bead-based immunoassays. Carriage density of and were assessed by quantitative PCR on genomic DNA extracted from nasopharyngeal swabs using species-specific primers and probes. All data were log-transformed for analysis using Student's unpaired t-tests with geometric mean titre (GMT) or density (GMD) calculated with 95% confidence intervals (CI). Serum -pneumococcal protein-specific IgG titres followed a \"U\" shaped pattern, with a decrease in presumably maternally-derived IgG titres between 1 and 4 months of age and returning to similar levels as those measured at 1 month of age by 24 months of age. In contrast, NTHi protein-specific IgG titres steadily increased with age. There was no correlation between antibody titres and carriage density for either pathogen. This longitudinal study indicates that the waning of maternally- derived antibodies that is usually observed in infants, after infants does not occur for NTHi antigens in Papua New Guinean infants. Whether NTHi antigen IgG can be transferred maternally remains to be determined. Vaccines that are designed to specifically increase the presence of protective NTHi antibodies in the first few months of life may be most effective in reducing NTHi disease. https://clinicaltrials.gov/, identifier NCT01619462.