Impact of intermittent preventive treatment in pregnancy with azithromycin-containing regimens on maternal nasopharyngeal carriage and antibiotic sensitivity of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus: a cross-sectional survey at delivery.

Sulfadoxine-pyrimethamine (SP) plus azithromycin (AZ) (SPAZ) has the potential for intermittent preventive treatment of malaria in pregnancy (IPTp), but its use could increase circulation of antibiotic-resistant bacteria associated with severe pediatric infections. We evaluated the effect of monthly SPAZ-IPTp compared to a single course of SP plus chloroquine (SPCQ) on maternal nasopharyngeal carriage and antibiotic susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus at delivery among 854 women participating in a randomized controlled trial in Papua New Guinea. Serotyping was performed, and antibiotic susceptibility was evaluated by disk diffusion and Etest. Potential risk factors for carriage were examined. Nasopharyngeal carriage at delivery of S. pneumoniae (SPAZ, 7.2% [30/418], versus SPCQ, 19.3% [84/436]; P<0.001) and H. influenzae (2.9% [12/418] versus 6.0% [26/436], P=0.028), but not S. aureus, was significantly reduced among women who had received SPAZ-IPTp. The number of macrolide-resistant pneumococcal isolates was small but increased in the SPAZ group (13.3% [4/30], versus SPCQ, 2.2% [2/91]; P=0.033). The proportions of isolates with serotypes covered by the 13-valent pneumococcal conjugate vaccine were similar (SPAZ, 10.3% [3/29], versus SPCQ, 17.6% [16/91]; P=0.352). Although macrolide-resistant isolates were rare, they were more commonly detected in women who had received SPAZ-IPTp, despite the significant reduction of maternal carriage of S. pneumoniae and H. influenzae observed in this group. Future studies on SPAZ-IPTp should evaluate carriage and persistence of macrolide-resistant S. pneumoniae and other pathogenic bacteria in both mothers and infants and assess the clinical significance of their circulation.

Pneumococcal carriage, serotype distribution, and antimicrobial susceptibility in Papua New Guinean children vaccinated with PCV10 or PCV13 in a head-to-head trial.

BACKGROUND: Children in Papua New Guinea (PNG) are at high risk of pneumococcal infections. We investigated pneumococcal carriage rates, serotype distribution, and antimicrobial susceptibility in PNG children after vaccination with 10-valent or 13-valent pneumococcal conjugate vaccines (PCV10; PCV13). METHODS: Infants (N = 262) were randomized to receive 3 doses of PCV10 or PCV13 at 1-2-3 months of age, followed by pneumococcal polysaccharide vaccination (PPV) or no PPV at 9 months of age. Nasopharyngeal swabs (NPS) collected at ages 1, 4, 9, 10, 23 and 24 months were cultured using standard bacteriological procedures. Morphologically distinct Streptococcus pneumoniae colonies were serotyped by the Quellung reaction. Antimicrobial susceptibility was determined by Kirby-Bauer disc diffusion and minimum inhibitory concentration (MIC). RESULTS: S. pneumoniae was isolated from 883/1063 NPS collected at 1-23 months of age, including 820 serotypeable (64 different serotypes) and 144 non-serotypeable isolates. At age 23 months, 93.6% (95%CI 86.6-97.6%) of PCV10 recipients and 88.6% (95%CI 80.1-94.4%) of PCV13 recipients were pneumococcal carriers, with higher carriage of PCV10 serotypes by PCV10 recipients (19.8%, 95%CI 12.2-29.5) than PCV13 recipients (9.3%, 95%CI 4.1-17.3) (p = 0.049). There were no other statistically significant differences between PCV10 and PCV13 recipients and children receiving PPV or no PPV. Nearly half (45.6%) of carried pneumococci were non-susceptible to penicillin based on the meningitis breakpoint (MIC ≥ 0.12 µg/mL), but resistance was rare (1.1%) using the non-meningitis cut-off (MIC ≥ 8 µg/mL). Non-susceptibility to trimethoprim-sulfamethoxazole (SXT) was common: 23.2% of isolates showed intermediate resistance (MIC 1/19-2/38 µg/mL) and 16.9% full resistance (MIC ≥ 4/76 µg/mL). PCV serotypes 14 and 19A were commonly non-susceptible to both penicillin (14, 97%; 19A, 70%) and SXT (14, 97%; 19A, 87%). CONCLUSION: Even after PCV10 or PCV13 vaccination, children living in a high-risk setting such as PNG continue to experience high levels of pneumococcal colonization, including carriage of highly antimicrobial-resistant PCV serotypes. The study is registered with ClinicalTrials.gov (CTN NCT01619462).

Panel 4: Recent advances in understanding the natural history of the otitis media microbiome and its response to environmental pressures.

OBJECTIVE: To perform a comprehensive review of otitis media microbiome literature published between 1st July 2015 and 30th June 2019. DATA SOURCES: PubMed database, National Library of Medicine. REVIEW METHODS: Key topics were assigned to each panel member for detailed review. Draft reviews were collated and circulated for discussion when the panel met at the 20th International Symposium on Recent Advances in Otitis Media in June 2019. The final draft was prepared with input from all panel members. CONCLUSIONS: Much has been learned about the different types of bacteria (including commensals) present in the upper respiratory microbiome, but little is known about the virome and mycobiome. A small number of studies have investigated the middle ear microbiome; however, current data are often limited by small sample sizes and methodological heterogeneity between studies. Furthermore, limited reporting of sample collection methods mean that it is often difficult to determine whether bacteria detected in middle ear fluid specimens originated from the middle ear or the external auditory canal. Recent in vitro studies suggest that bacterial interactions in the nasal/nasopharyngeal microbiome may affect otitis media pathogenesis by modifying otopathogen behaviours. Impacts of environmental pressures (e.g. smoke, nutrition) and clinical interventions (e.g. vaccination, antibiotics) on the upper respiratory and middle ear microbiomes remain poorly understood as there are few data. IMPLICATIONS FOR PRACTICE: Advances in understanding bacterial dynamics in the upper airway microbiome are driving development of microbiota-modifying therapies to prevent or treat disease (e.g. probiotics). Further advances in otitis media microbiomics will likely require technological improvements that overcome the current limitations of OMICs technologies when applied to low volume and low biomass specimens that potentially contain high numbers of host cells. Improved laboratory models are needed to elucidate mechanistic interactions among the upper respiratory and middle ear microbiomes. Minimum reporting standards are critically needed to improve inter-study comparisons and enable future meta-analyses.

Limited impact of neonatal or early infant schedules of 7-valent pneumococcal conjugate vaccination on nasopharyngeal carriage of Streptococcus pneumoniae in Papua New Guinean children: A randomized controlled trial.

Streptococcus pneumoniae is a leading cause of pneumonia, the most common cause of childhood death. Papua New Guinean children experience high rates of nasopharyngeal pneumococcal colonization within weeks of birth, predisposing them to pneumococcal disease. In a trial to determine the safety and immunogenicity of early infant vaccination with 7-valent pneumococcal conjugate vaccine (7vPCV), we investigated the impact of early schedules on pneumococcal carriage. Infants were randomized at birth to receive 7vPCV in a 0-1-2-month (n = 101) or a 1-2-3-month (n = 105) schedule or no 7vPCV (n = 106). All children received 23-valent pneumococcal polysaccharide vaccine at age 9 months. We cultured nasopharyngeal swabs (NPS) collected at ages 1, 2, 3, 4 weeks and 3, 9, 18 months, and middle ear discharge if present. Pneumococcal serotypes were identified by the Quellung reaction. A total of 1761 NPS were cultured. The prevalence of pneumococcal carriage was 22% at 1 week of age, rising to 80% by age 3 months and remained >70% thereafter, with high-density carriage in 42% of pneumococcus-positive samples. We identified 63 different serotypes; 43% of isolates from controls were 13vPCV serotypes. There were no significant differences in 7vPCV serotype carriage between 7vPCV recipients and controls at any age (22% vs. 31% at 9 months, p = 0.2). At age 9 months the prevalence of non-7vPCV carriage was 17% higher in 7vPCV recipients (48%) than in controls (25%, p = 0.02). More non-7vPCV serotypes were isolated from ear discharge in 16 7vPCV recipients than from 4 controls (48% vs. 25%, p = 0.13). The limited impact of neonatal or accelerated infant 7vPCV schedules on vaccine serotype carriage is probably due to the early onset of dense carriage of a broad range of pneumococcal serotypes. While serotype-independent pneumococcal vaccines are needed in high-risk populations, the underlying environmental factors and sources of infection must be investigated. http://clinicaltrials.gov/ct2/show/NCT00219401.

A Synthetic Virus-Like Particle Streptococcal Vaccine Candidate Using B-Cell Epitopes from the Proline-Rich Region of Pneumococcal Surface Protein A.

Alternatives to the well-established capsular polysaccharide-based vaccines against Streptococcus pneumoniae that circumvent limitations arising from limited serotype coverage and the emergence of resistance due to capsule switching (serotype replacement) are being widely pursued. Much attention is now focused on the development of recombinant subunit vaccines based on highly conserved pneumococcal surface proteins and virulence factors. A further step might involve focusing the host humoral immune response onto protective protein epitopes using as immunogens structurally optimized epitope mimetics. One approach to deliver such epitope mimetics to the immune system is through the use of synthetic virus-like particles (SVLPs). SVLPs are made from synthetic coiled-coil lipopeptides that are designed to spontaneously self-assemble into 20-30 nm diameter nanoparticles in aqueous buffer. Multivalent display of epitope mimetics on the surface of SVLPs generates highly immunogenic nanoparticles that elicit strong epitope-specific humoral immune responses without the need for external adjuvants. Here, we set out to demonstrate that this approach can yield vaccine candidates able to elicit a protective immune response, using epitopes derived from the proline-rich region of pneumococcal surface protein A (PspA). These streptococcal SVLP-based vaccine candidates are shown to elicit strong humoral immune responses in mice. Following active immunization and challenge with lethal doses of streptococcus, SVLP-based immunogens are able to elicit significant protection in mice. Furthermore, a mimetic-specific monoclonal antibody is shown to mediate partial protection upon passive immunization. The results show that SVLPs combined with synthetic epitope mimetics may have potential for the development of an effective vaccine against Streptococcus pneumoniae.

Effect of early carriage of Streptococcus pneumoniae on the development of pneumococcal protein-specific cellular immune responses in infancy.

BACKGROUND: The aim of this study was to examine the relationship between nasopharyngeal pneumococcal colonization in early life and the subsequent development of pneumococcal-specific T cell responses. METHODS: Pernasal swabs were collected from Papua New Guinean infants at the ages of 1 and 2 weeks (n = 279). At 9 months, in vitro cellular immune responses to choline-binding protein A (n = 132), pneumococcal surface protein A (n = 132), pneumolysin (n = 99), and the pneumococcal conjugate vaccine carrier CRM197 were determined. Responses were compared based on the children's carriage status within the first 2 weeks of life. RESULTS: Within the first 2 weeks of life, 40% of the study children carried Streptococcus pneumoniae. Early carriage was associated with lower interferon-γ and interleukin 10 responses to pneumococcal proteins at age 9 months when children had not received pneumococcal conjugate vaccines during the study period. CONCLUSIONS: Early pneumococcal carriage may result in enhanced disease susceptibility and suboptimal vaccine responses by modulating the development of pneumococcal immune responses.