Biofilm production by Haemophilus influenzae and Streptococcus pneumoniae isolated from the nasopharynx of children with acute otitis media.

BACKGROUND: Biofilm production by Haemophilus influenzae and Streptococcus pneumoniae has been implicated in the pathogenesis of otitis media, mainly in chronic and recurrent cases. We studied the "in vitro" biofilm production by these 2 species isolated alone or together from the nasopharynx of children with acute otitis media. METHODS: The studied strains were from 3 pneumococcal conjugate vaccine (PCV) periods: pre-PCV7, post-PCV7/pre-PCV13 and post-PCV13. A modified microtiter plate assay with crystal violet stain was used to study the biofilm production of 182 H. influenzae and 191 S. pneumoniae strains. RESULTS: Overall, 117/181 (64.6%) H. influenzae and 128/191 (66.8%) S. pneumoniae strains produced biofilm. The proportion of biofilm-producing H. influenzae strains was greater with than without the isolation of S. pneumoniae in the same sample (75.5% vs 52.3%, p = 0.001). Conversely, the proportion of biofilm-producing S. pneumoniae strains was not affected by the presence or not of H. influenzae (66.3% vs 67.4%). S. pneumoniae serotypes 6B, 15B/C, 19A, 35F and 35B were the better biofilm producers (80%). Serotypes 11A, 14, 15A, 19F and 19A were more associated with H. influenzae biofilm-producing strains. Overall, 89/94 (94.6%) of cases with combined isolation showed biofilm production by S. pneumoniae or H. influenzae. CONCLUSION: This study emphasizes the high proportion of biofilm production by H. influenzae and S. pneumoniae strains isolated from the nasopharynx of children with acute otitis media, which reinforces the results of studies suggesting the importance of biofilm in the pathogenesis of acute otitis media.

Assessment of an optimized manufacturing process for inactivated quadrivalent influenza vaccine: a phase III, randomized, double-blind, safety and immunogenicity study in children and adults.

BACKGROUND: GSK has modified the licensed monovalent bulk manufacturing process for its split-virion inactivated quadrivalent influenza vaccine (IIV4) to harmonize the process among different strains, resulting in an increased number of finished vaccine doses, while compensating for the change from inactivated trivalent influenza vaccine (IIV3) to IIV4. To confirm the manufacturing changes do not alter the profile of the vaccine, a clinical trial was conducted to compare IIV4 made by the currently licensed process with a vaccine made by the new (investigational) process (IIV4-I). The main objectives were to compare the reactogenicity and safety of IIV4-I versus IIV4 in all age groups, and to demonstrate the non-inferiority of the hemagglutination-inhibition (HI) antibody responses based on the geometric mean titer ratio of IIV4-I versus IIV4 in children. METHODS: The Phase III, randomized, double-blind, multinational study included three cohorts: adults (18-49 years; N = 120), children (3-17 years; N = 821), and infants (6-35 months; N = 940). Eligible subjects in each cohort were randomized 1:1 to receive IIV4-I or IIV4. Both vaccines contained 15 µg of hemagglutinin antigen for each of the four seasonal virus strains. Adults and vaccine-primed children received one dose of vaccine, and vaccine-unprimed children received two doses of vaccine 28 days apart. All children aged ≥9 years were considered to be vaccine-primed and received one dose of vaccine. RESULTS: The primary immunogenicity objective of the study was met in demonstrating immunogenic non-inferiority of IIV4-I versus IIV4 in children. The IIV4-I was immunogenic against all four vaccine strains in each age cohort. The reactogenicity and safety profile of IIV4-I was similar to IIV4 in each age cohort, and there was no increase in the relative risk of fever (≥38 °C) with IIV4-I versus IIV4 within the 7-day post-vaccination period in infants (1.06; 95% Confidence Interval: 0.75, 1.50; p = 0.786). CONCLUSIONS: The study demonstrated that in adults, children, and infants, the IIV4-I made using an investigational manufacturing process was immunogenic with a reactogenicity and safety profile that was similar to licensed IIV4. These results support that the investigational process used to manufacture IIV4-I is suitable to replace the current licensed process. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02207413 ; trial registration date: August 4, 2014.

ESBL-producing Escherichia coli ST131 versus non-ST131: evolution and risk factors of carriage among French children in the community between 2010 and 2015.

OBJECTIVES: The objective of this study was to evaluate the evolution and risk factors of ESBL-producing Enterobacteriaceae (ESBL-E) carriage in children in the community for a long period distinguishing ST131 and non-ST131 Escherichia coli. PATIENTS AND METHODS: In this prospective study, rectal samples were obtained from children aged 6-24 months by community paediatricians between 2010 and 2015. Demographic characteristics and risk factors for ESBL-E carriage were collected. Distribution of ß-lactamase genes, phylogenetic groups, ST131 and virulence factors of resistant E. coli was determined. RESULTS: We enrolled 1886 children; 144 (7.6%) harboured ESBL-E, and this rate increased from 4.8% to 10.2% between 2010 and 2015. Risk factors for ESBL-E carriage were being cared for at home [adjusted OR (aOR) = 1.8, 95% CI = 1.1-2.9], recent antibiotic use (aOR = 1.5, 95% CI = 1.0-2.1) and travel history (aOR = 1.7, 95% CI = 1.1-2.6). Among patients carrying ESBL, E. coli (98%) and CTX-M type (90%) predominated and PapGII adhesin, characteristic of pyelonephritogenic E. coli strains, was rare (7%). In 2015, E. coli isolates frequently belonged to the phylogenetic group B2 (48%), and 37% were ST131 compared with 5% in 2010. Compared with non-ESBL-producing strains, ST131 carriage was associated with hospitalization in the last 6 months (aOR = 3.5, 95% CI = 1.4-8.8). CONCLUSIONS: Between 2010 and 2015, the carriage of ESBL-E in community children doubled because of the massive expansion of the E. coli ST131 clonal group. The risk for carrying ST131 was associated with previous hospitalization, but not, contrary to the counterpart, antibiotic treatment, daycare attendance or travel history.

Selective testing strategies for diagnosing group A streptococcal infection in children with pharyngitis: a systematic review and prospective multicentre external validation study.

BACKGROUND: Several clinical prediction rules for diagnosing group A streptococcal infection in children with pharyngitis are available. We aimed to compare the diagnostic accuracy of rules-based selective testing strategies in a prospective cohort of children with pharyngitis. METHODS: We identified clinical prediction rules through a systematic search of MEDLINE and Embase (1975-2014), which we then validated in a prospective cohort involving French children who presented with pharyngitis during a 1-year period (2010-2011). We diagnosed infection with group A streptococcus using two throat swabs: one obtained for a rapid antigen detection test (StreptAtest, Dectrapharm) and one obtained for culture (reference standard). We validated rules-based selective testing strategies as follows: low risk of group A streptococcal infection, no further testing or antibiotic therapy needed; intermediate risk of infection, rapid antigen detection for all patients and antibiotic therapy for those with a positive test result; and high risk of infection, empiric antibiotic treatment. RESULTS: We identified 8 clinical prediction rules, 6 of which could be prospectively validated. Sensitivity and specificity of rules-based selective testing strategies ranged from 66% (95% confidence interval [CI] 61-72) to 94% (95% CI 92-97) and from 40% (95% CI 35-45) to 88% (95% CI 85-91), respectively. Use of rapid antigen detection testing following the clinical prediction rule ranged from 24% (95% CI 21-27) to 86% (95% CI 84-89). None of the rules-based selective testing strategies achieved our diagnostic accuracy target (sensitivity and specificity>85%). INTERPRETATION: Rules-based selective testing strategies did not show sufficient diagnostic accuracy in this study population. The relevance of clinical prediction rules for determining which children with pharyngitis should undergo a rapid antigen detection test remains questionable.

Rapid-antigen detection tests for group a streptococcal pharyngitis: revisiting false-positive results using polymerase chain reaction testing.

We investigated mechanisms of the false-positive test results on rapid-antigen detection test (RADT) for group A Streptococcal (GAS) pharyngitis. Most RADT false-positives (76%) were associated with polymerase chain reaction-positive GAS results, suggesting that RADT specificity could be considered close to 100%. Finding that 61% of GAS culture-negative but RADT-positive cases were positive on both GAS polymerase chain reaction and Staphylococcus aureus testing, we posit bacterial inhibition as causative.

Anti-infective treatment of gastro-intestinal tract infections in children.

Gastroenteritis is most often viral in origin and Rotavirus and Norovirus most frequently implicated in young children. Stool-based multiplex Polymerase Chain Reaction (PCR) can detect bacteria, viruses or parasites that may or may not be responsible for gastroenteritis (colonization). While the etiological profile of these digestive infections has greatly benefited from PCR, in the absence of underlying pathologies the presence of potential pathogens does not justify anti-infectious treatment. Indeed, very few bacterial causes require antibiotic treatment, apart from shigellosis, severe forms of salmonellosis and a few Campylobacter sp. infections. The development of antibiotic resistance in Salmonella sp., Shigella sp. and Campylobacter sp. is a cause for concern worldwide, limiting therapeutic options. The antibiotics proposed in this guide are in line with the joint recommendations of the European Society of Pediatric Infectious Diseases and the European Society of Pediatric Gastroenterology and Nutrition. Azithromycin is preferentially used to treat infections with Shigella sp. or Campylobacter sp. Ceftriaxone and ciprofloxacin are recommended for salmonellosis requiring antibiotic therapy. Empirical treatments without bacterial identification are not indicated except in cases of severe sepsis or in subjects at risk (e.g., sickle-cell disease). Metronidazole should be prescribed only for acute intestinal amebiasis after microbiological confirmation.

Otorrhea bacterial profile, epidemiology before widespread use of the third-generation pneumococcal conjugate vaccine in French children, a prospective study from 2015 to 2023.

OBJECTIVES: The aim of this study was to describe the bacterial profile of middle ear fluid from spontaneous perforation of the tympanic membrane (SPTM) prior to widespread utilization of third- generation pneumococcal conjugate vaccines (PCVs). PATIENTS AND METHODS: From October 2015 to January 2023, children with SPTM were prospectively enrolled by pediatricians. RESULTS: Among the 852 children with SPTM, 73.2% were less than 3 years old; more frequently than older children, they were and suffering from complex acute otitis media (AOM) (27.9%) and conjunctivitis (13.1%). In children under 3 years of age, NT Haemophilus influenzae (49.7%) was the main otopathogen isolated, particularly in those with complex AOM (57.1%). In children over 3 years of age, Group A Streptococcus accounted for 57%. In pneumococcal cases (25.1%), serotype 3 was the main serotype isolated (16.2%), followed by 23B (15.2%). CONCLUSION: Our data from 2015 to 2023 represent a robust baseline preceding the widespread utilization of next-generation PCVs.

Decline in macrolide-resistant Streptococcus pyogenes isolates from French children.

We studied the macrolide resistance and serotypes of 585 group A streptococcus (GAS) isolates collected from French children with pharyngitis. Nineteen isolates (3.2%) were erythromycin-resistant and harbored the following resistance genes: 31.6% mef(A), 15.8% erm(A), and 52.6% erm(B). The 19 isolates included 7 different emm types (4, 1, 11, 2, 28, 12, and 77) and 7 corresponding multilocus sequence types. The current fall in macrolide consumption has led to a very low rate of GAS macrolide resistance.

Nasopharyngeal flora in children with acute otitis media before and after implementation of 7 valent pneumococcal conjugate vaccine in France.

BACKGROUND: Several studies have investigated the impact of 7-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal (Sp) and staphylococcal (Sa) nasopharyngeal (NP) carriage. Few have investigated the impact on Haemophilus influenzae (Hi) and Moraxella catarrhalis (Mc) carriage. We aimed to compare the NP carriage rates in young children with acute otitis media (AOM) before and after PCV7 implementation in France. METHODS: Prior to PCV7 implementation, we performed 4 successive randomized trials with NP samples. These studies compared several antibiotic regimens for treating AOM in young children (6 to 30 months). After PCV7 implementation, to assess the impact of the vaccination program on NP flora, young children with AOM were enrolled in a prospective surveillance study. In each study, we obtained an NP sample to analyze the carriage rates of Sp, Hi, Mc and Sa and the factors influencing the carriage. Standardized history and physical examination findings were recorded; the methods used for NP swabs (sampling and cultures) were the same in all studies. RESULTS: We enrolled 4,405 children (mean age 13.9 months, median 12.8). Among the 2,598 children enrolled after PCV7 implementation, 98.3% were vaccinated with PCV7. In comparing the pre- and post-PCV7 periods, we found a slight but non-significant decrease in carriage rates of pneumococcus (AOR = 0.85 [0.69;1.05]), H. influenzae (AOR = 0.89 [0.73;1.09]) and S. aureus (AOR = 0.92 [0.70;1.19]). By contrast, the carriage rate of M. catarrhalis increased slightly but not significantly between the 2 periods (AOR = 1.08 [0.95;1.2]). Among Sp carriers, the proportion of PCV7 vaccine types decreased from 66.6% to 10.7% (P < 0.001), penicillin intermediate-resistant strains increased from 30.3% to 43.4% (P < 0.001), and penicillin-resistant strains decreased greatly from 22.8% to 3.8% (P < 0.001). The proportion of Hi ß-lactamase-producing strains decreased from 38.6% to 17.1% (P < 0.001). CONCLUSION: The carriage rates of otopathogen species (Sp, Hi, Mc) and Sa did not significantly change in children with AOM after PCV7 implementation in France. However, we observed significant changes in carriage rates of PCV7 vaccine serotypes and penicillin non-susceptible Sp.

Community faecal carriage of extended-spectrum beta-lactamase-producing Enterobacteriaceae in French children.

BACKGROUND: The increasing incidence of community acquired infection due to Extended-Spectrum Beta-Lactamase (ESBL) -Producing Enterobacteriaceae represent a great concern because there are few therapeutic alternatives. The fecal flora of children in the community can represent a reservoir for ESBLs genes which are located on highly transmissible plasmids and the spread of these genes among bacterial pathogens is concerning. Because intestinal carriage is a key factor in the epidemiology of ESBL-producing Enterobacteriaceae, the study of the prevalence of these resistant bacteria and risk factors in young children is of particular interest. METHODS: We assessed the prevalence and risk factors of community-acquired faecal carriage of extended-spectrum-ß-lactamase (ESBL)-producing Enterobacteriaceae in children aged from 6 to 24 months, by means of rectal swabbing in community pediatric practices. Child's lifestyle and risk factors for carriage of resistant bacteria were noted. RESULTS: Among the 411 children enrolled, 4.6% carried ESBL-producing Enterobacteriaceae. CTX-M-1, CTX-M-15 and CTX-M-14 were the predominant ESBLs. The 18 E. coli isolates were genetically heterogeneous. Recent third-generation oral-cephalosporin exposure was associated with a higher risk of ESBL carriage (AOR=3.52, 95% CI[1.06-11.66], p=0.04). CONCLUSIONS: The carriage rate of ESBL-producing Enterobacteriacae in young children in the French community setting is noteworthy, underlining the importance of this population as a reservoir. Exposure to third-generation oral cephalosporins was associated with a significant risk of ESBL carriage in our study. Because of the significant public health implications including the treatment of community-acquired urinary tract infections, the spread of organisms producing ESBLs in the community merits close monitoring with enhanced efforts for surveillance.

Risk factors for serotype 19A carriage after introduction of 7-valent pneumococcal vaccination.

BACKGROUND: After the implementation of 7-valent pneumococcal conjugate vaccine (PCV7), in several countries, serotype 19A is now the serotype most frequently involved in pneumococcal diseases and carriage. To determine factors potentially related to 19A nasopharyngeal (NP) carriage we analyzed data from an ongoing prospective French national surveillance study of pneumococcal NP carriage in young children. METHODS: NP swabs were obtained from children aged 6 to 24 months, either during routine check-ups with normal findings, or when they presented with acute otitis media (AOM). The swabs were sent for analysis to the French National Reference Centre for Pneumococci. Factors influencing pneumococcal carriage and carriage of penicillin non-susceptible (PNSP), 19A and PNS-19A were investigated by multivariate logistic regression. RESULTS: From 2006 to 2009, 66 practitioners enrolled 3507 children (mean age 13.6 months), of whom, 98.3% of children had been vaccinated with PCV7 and 33.4% of children attended daycare centres (DCC). Serotype 19A was found in 10.4% of the overall population, 20.5% of S. pneumoniae carriers (n = 1780) and 40.8% of PNSP carriers (n = 799). Among 19A strains, 10.7% were penicillin-susceptible, 80% intermediate and 9.3% fully resistant. Logistic regression analysis showed that the main factors associated with PNSP carriage were AOM (OR = 3.09, 95% CI [2.39;3.98]), DCC (OR = 1.70, 95% CI [1.42;2.03]), and recent antibiotic use (OR = 1.24, 95% CI [1.05;1.47]. The main factors predictive of 19A carriage were recent antibiotic use (OR = 1.81, 95% CI [1.42;2.30]), AOM (OR = 1.67, 95% CI [1.11;2.49]), DCC (OR = 1.56, 95% CI [1.21;2.2] and young age, <12 months (OR = 1.51, 95% CI [1.16;1.97]). CONCLUSION: In a population of children aged from 6 to 24 months with a high rate of PCV7 vaccination coverage, we found that antibiotic exposure, DCC attendance and AOM were linked to 19A carriage.

Young children formula consumption and iron deficiency at 24 months in the general population: A national-level study.

BACKGROUND & AIMS: Iron deficiency (ID) is considered the most frequent micronutrient deficiency in industrialized countries where strategies for its primary prevention vary widely and are insufficiently evaluated. We aimed to study the effectiveness for iron status of a national iron deficiency prevention strategy based on recommendations for young-child formula (YCF) use after age 12 months, taking into consideration other sources of iron and the family's socio-economic status. METHODS: In a cross-sectional observational study conducted in primary care pediatrician offices throughout France from 2016 to 2017, infants aged 24 months were consecutively included for a food survey and blood sampling. Associations between YCF consumption and serum ferritin (SF) level were studied by multivariable regression after adjustment on sociodemographic, perinatal and dietary characteristics, notably other intakes of iron. RESULTS: Among the 561 infants analyzed, the ID prevalence was 6.6% (37/561; 95% confidence interval [CI] 4.7-9.0). Daily iron intake excluding YCF and total daily iron intake including YCF were below the 5-mg/day recommended average requirements for 63% and 18% of children, respectively. ID frequency was significantly decreased (or SF level was independently higher) with any YCF consumption after age 10 months (odds ratio 0.15, 95% CI 0.07-0.31), current YCF consumption at age 24 months (median SF level 29 vs 21 µg/L if none), prolonged YCF consumption (28 µg/L if >12 months vs 17 µg/L if none), and increasing daily volume of YCF consumed at age 24 months from a small volume (e.g., 29 µg/L if <100 mL/day vs 21 µg/L if none). CONCLUSIONS: Current or past YCF use was independently associated with a better iron status at age 24 months than non-use. The strategy recommending YCF use at weaning after age 12 months seems effective in the general population. CLINICALTRIALS. GOV IDENTIFIER: NCT02484274.

Bacterial causes of otitis media with spontaneous perforation of the tympanic membrane in the era of 13 valent pneumococcal conjugate vaccine.

After pneumococcal conjugate vaccine (PCV) implementation, the number of acute otitis media (AOM) episodes has decreased, but AOM still remains among the most common diagnoses in childhood. From 2% to 17% of cases of AOM feature spontaneous perforation of the tympanic membrane (SPTM). The aim of this study was to describe the bacteriological causes of SPTM 5 to 8 years years after PCV13 implementation, in 2010. From 2015 to 2018, children with SPTM were prospectively enrolled by 41 pediatricians. Middle ear fluid was obtained by sampling spontaneous discharge. Among the 470 children with SPTM (median age 20.8 months), no otopathogen was isolated for 251 (53.4% [95% CI 48.8%;58.0%]): 47.1% of infants and toddlers, 68.3% older children (p<0.001). Among children with isolated bacterial otopathogens (n = 219), non-typable Haemophilus influenzae (NTHi) was the most frequent otopathogen isolated (n = 106, 48.4% [95% CI 41.6%;55.2%]), followed by Streptoccocus pyogenes (group A streptococcus [GAS]) (n = 76, 34.7% [95% CI 28.4%;41.4%]) and Streptococcus pneumoniae (Sp) (n = 61, 27.9% [95% Ci 22.0%;34.3%]). NTHi was frequently isolated in infants and toddlers (53.1%), whereas the main otopathogen in older children was GAS (52.3%). In cases of co-infection with at least two otopathogens (16.9%, n = 37/219), NTHi was frequently involved (78.4%, n = 29/37). When Sp was isolated, PCV13 serotypes accounted for 32.1% of cases, with serotype 3 the main serotype (16.1%). Among Sp strains, 29.5% were penicillin-intermediate and among NTHi strains, 16.0% were ß-lactamase-producers. More than 5 years after PCV13 implementation, the leading bacterial species recovered from AOM with SPTM was NTHi for infants and toddlers and GAS for older children. In both age groups, Sp was the third most frequent pathogen and vaccine serotypes still played an important role. No resistant Sp strains were isolated, and the frequency of ß-lactamase-producing NTHi did not exceed 16%.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and 4vHPV vaccine administered according to two- or three-dose schedules in girls aged 9-14 years: Results to month 36 from a randomized trial.

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of two doses (2D) of the HPV-16/18 AS04-adjuvanted vaccine (2D of AS04-HPV-16/18) vs. two or three doses of the 4vHPV vaccine [2D or 3D of 4vHPV] in 1075 healthy girls aged 9-14 years. Girls were randomized (1:1:1) to receive 2D of AS04-HPV-16/18 at months (M) 0, 6 (N = 359), 2D of 4vHPV at M0, 6 (N = 358) or 3D of 4vHPV at M0, 2, 6 (N = 358). 351, 339 and 346 girls, respectively, returned for the concluding visit at M36. Superiority was demonstrated at M7 and M12; comparison of the immune response to both vaccine antigens was made between 2D of AS04-HPV-16/18 and 2D or 3D of 4vHPV at subsequent time points in the according-to-protocol immunogenicity cohort (ATP-I; N = 958 at M36) and the total vaccinated cohort (TVC: N = 1036 at M36). HPV-16/18-specific T-cell- and B-cell-mediated immune responses and safety were also investigated. At M36, anti-HPV-16/18 ELISA responses in the 2D AS04-HPV-16/18 group remained superior to those of the 2D and 3D 4vHPV groups. In the M36 TVC, geometric mean titers were 2.78-fold (HPV-16) and 6.84-fold (HPV-18) higher for 2D of AS04-HPV-16/18 vs. 2D of 4vHPV and 2.3-fold (HPV-16) and 4.14-fold (HPV-18) higher vs. 3D of 4vHPV. Results were confirmed by vaccine pseudovirion-based neutralisation assay. Numbers of circulating CD4+ T cells and B cells appeared similar across groups. Safety was in line with the known safety profiles of both vaccines. In conclusion, superior HPV-16/18 antibody responses were elicited by 2D of the AS04-HPV-16/18 compared with 2D or 3D of the 4vHPV vaccine in girls aged 9-14 years. CLINICAL TRIAL REGISTRATION: NCT0146235.

Pneumococcal conjugate vaccine does not influence Staphylococcus aureus carriage in young children with acute otitis media.

We investigated nasopharyngeal carriage of Streptococcus pneumoniae and Staphylococcus aureus among infants and young children with acute otitis media in a country where use of 7-valent pneumococcal conjugate vaccine (PCV7) has been progressively implemented. Among 1783 children enrolled, 60.8% carried S. pneumoniae, and 9% carried S. aureus. Among S. pneumoniae carriers, the rate of S. aureus carriage was 8.4%, compared with 9.9% among S. pneumoniae noncarriers. The rate of S. pneumoniae carriage in the PCV7-vaccinated population was lower (59.8%) than that observed in the nonvaccinated population (66.2%; P<.04). In contrast, in young children (age, <2 years) with acute otitis media, our study suggests that the S. aureus carriage rate is not affected by PCV7 immunization (9.0% in vaccinated children vs. 8.7% in nonvaccinated children). Furthermore, in children aged >1 year, the booster dose induces a sharp reduction in the carriage of vaccine serotypes of S. pneumoniae, without any change in S. aureus carriage.

A 13-year survey of pneumococcal nasopharyngeal carriage in children with acute otitis media following PCV7 and PCV13 implementation.

BACKGROUND: This nasopharyngeal (NP) carriage surveillance study was requested by the European Agency for the Evaluation of Medicinal Products as a post-licensing commitment to determine whether the use of the pneumococcal conjugate vaccines (PCVs) including 7 then 13 valents (introduced in 2001 and 2010, respectively) caused a shift in the distribution of Streptococcus pneumoniae serotypes in children with acute otitis media and modified the resistance of this bacterial species to antibiotics. METHODS: Between 2001 and 2014, 121 pediatricians obtained nasopharyngeal swabs from children with acute otitis media aged 6-24 months. The swabs were analyzed by the French National Reference Centre for Pneumococci. Demographics, medical history and physical examination findings were recorded. RESULTS: Over the 13 years, among the 7991 enrolled patients, the proportion of PCV-vaccinated children (≥1 dose) increased (54.3-99.7%, p<0.001). Overall, pneumococcal carriage was reduced from 71.2% to 56.2% from 2001 to 2014 (p<0.001) and carriage of PCV7 serotypes (STs) from 44.5% to 1.2% (p<0.001). The carriage of 6 additional STs plus 6C increased from 17.2% to 24.3% from 2001 to 2010 (p<0.001) and decreased after PCV13 implementation (21.4-3.5%, p<0.001). The proportion of ST 19A carriage increased from 8.6% to 15.8% from 2001 to 2010 (p<0.001) and decreased to 1.2% in 2014. After PCV13 implementation, the most frequently carried non-PCV13 STs were ST 15B/C, 11A, 15A, and 35B. Penicillin non-susceptible pneumococcal strains decreased from 67.1% in 2001 to 33.1% in 2014 (p<0.001). CONCLUSIONS: By the number of patients enrolled and the duration, this study is the largest performed to date. It allows to demonstrate a strong impact of PCVs and to describe the complex dynamics of pneumococcal carriage during AOM. As pneumococcal carriage decreased during AOM, a reduction in the incidence of pneumococcal AOM could be expected.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine administered according to 2- and 3-dose schedules in girls aged 9-14 years: Results to month 12 from a randomized trial.

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of 2 doses of the HPV-16/18 AS04-adjuvanted vaccine (HPV-16/18(2D)) vs. 2 or 3 doses of the HPV-6/11/16/18 vaccine (HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D)) in healthy girls aged 9-14 y. Girls were randomized (1:1:1) to receive HPV-16/18(2D) at months (M) 0,6 (N = 359), HPV-6/11/16/18(2D) at M0,6 (N = 358) or HPV-6/11/16/18(3D) at M0,2,6 (N = 358). The primary objective was non-inferiority/superiority of HPV-16/18 antibodies by ELISA for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) at M7 in the according-to-protocol immunogenicity cohort (ATP-I) and total vaccinated cohort, respectively. Secondary objectives included non-inferiority/superiority of HPV-16/18(2D) vs. HPV-6/11/16/18(3D) at M7, non-inferiority/superiority at M12, HPV-16/18 neutralizing antibodies, frequencies of T-cells/B-cells, reactogenicity and safety. Antibody responses at M7 for HPV-16/18(2D) were superior to those for HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) (lower limit of 95% confidence interval for geometric mean titer ratio (GMR) was >1): HPV-16/18(2D)/HPV-6/11/16/18(2D) GMRs were 1.69 [1.49-1.91] for anti-HPV-16 and 4.52 [3.97-5.13] for anti-HPV-18; HPV-16/18(2D)/HPV-6/11/16/18(3D) GMRs were 1.72 [1.54-1.93] for anti-HPV-16 and 3.22 [2.82-3.68] for anti-HPV-18; p = 0.0001 for all comparisons. Non-inferiority/superiority was also demonstrated at M12. Among initially seronegative girls in the ATP-I, neutralizing antibody titers were at least 1.8-fold higher for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) at M7 and M12. Frequencies of HPV-16/18-specific T-cells and B-cells were in similar ranges between groups. Reactogenicity and safety were in line with the known profile of each vaccine. In conclusion, superior HPV-16/18 antibody responses were elicited by 2 doses of the HPV-16/18 AS04-adjuvanted vaccine compared with 2 or 3 doses of the HPV-6/11/16/18 vaccine in girls (9-14 years).

A randomized study to evaluate the immunogenicity and safety of a heptavalent diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, haemophilus influenzae b, and meningococcal serogroup C combination vaccine administered to infants at 2, 4 and 12 months of age.

BACKGROUND: The immunogenicity and safety of the investigational diphtheria, tetanus, acellular pertussis, hepatitis B, poliomyelitis, Haemophilus influenzae type b (Hib) and meningococcal serogroup C (MenC) heptavalent combination vaccine were compared with those of licensed control vaccines. METHODS: In this open, phase II, randomized study (NCT01090453), 480 infants from Germany, France and Canada received the heptavalent vaccine (Hepta group) or hexavalent and monovalent MenC control vaccines (HexaMenC group) co-administered with a 13-valent pneumococcal conjugate vaccine at 2, 4 and 12 months of age. Immunogenicity was measured 1 month after the second primary dose, and before and 1 month after the booster dose. Safety and reactogenicity were also evaluated. RESULTS: Non-inferiority of immune responses to MenC and Hib induced by 2-dose primary vaccination with the heptavalent vaccine versus control vaccines was demonstrated. In exploratory analyses, postprimary and postbooster functional antibody geometric mean titers against MenC tended to be lower (1119.5 vs. 3200.5; 2653.8 vs. 6028.4) and antibody geometric mean concentrations against Hib higher (1.594 vs. 0.671 µg/mL; 17.678 vs. 13.737 µg/mL) in the Hepta versus the HexaMenC group. The heptavalent and control vaccines were immunogenic to all other antigens, although immune responses to poliovirus were lower than expected in both groups. No differences in safety and reactogenicity profiles were detected between groups. CONCLUSIONS: The heptavalent vaccine induced non-inferior MenC and Hib responses compared with control vaccines. Both vaccination regimens, when administered at 2, 4 and 12 months of age, had comparable safety profiles and were immunogenic to all antigens, with lower-than-expected responses to poliomyelitis.

Probiotics and prebiotics in preventing episodes of acute otitis media in high-risk children: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Several studies have suggested that probiotics (proB) and/or prebiotics (preB) could reduce the burden of infection in infants and toddlers. We aimed to determine whether follow-up formula supplemented with proB and preB could reduce the risk of acute otitis media (AOM). METHODS: In this double-blind, placebo-controlled trial from November 2007 to April 2009, 37 pediatricians in France enrolled children 7 to 13 months of age with high risk of AOM who were randomly assigned to receive follow-up formula supplemented with proB (Streptococcus thermophilus NCC 2496, Streptococcus salivarius DSM 13084, Lactobacillus rhamnosus LPR CGMCC 1.3724) and preB (Raftilose/Raftiline) or follow-up formula alone (placebo). During 12 months, the 2 groups were compared for number of AOM episodes diagnosed (primary outcome) and secondary outcomes by the Poisson model (incidence rate ratio [IRR]) or logistic regression (odds ratio; and 95% confidence interval [95% CI]) after adjustment on covariates of interest. RESULTS: We enrolled 224 children (112 in each group). All children were vaccinated (4 doses) with the 7-valent pneumococcal conjugate vaccine; demographic characteristics were similar in the 2 groups. In total, 486 AOM episodes were reported, 249 and 237 in the treatment and control groups, respectively. The treatment and control groups did not differ in incidence of AOM (IRR 1.0, 95% CI: 0.8-1.2), lower respiratory tract infections (IRR 0.9, 0.7-1.2) or number of antibiotic treatment courses (IRR = 1.0, 95% CI: 0.8-1.2). Treatment was not associated with recurrent AOM (odds ratio 1.0, 95% CI: 0.5-1.7). With regard to gastrointestinal disorders, both formulas were well tolerated. CONCLUSION: The proB and preB included in follow-up formula given to children at 7 to 13 months of age did not reduce the risk of AOM, recurrent AOM, antibiotic use or lower respiratory tract infections at 1 year.