Natural carriage of Streptococcus pneumoniae is associated with increased experimental pneumococcal carriage but reduced conjugate vaccine efficacy in a human challenge model.

BACKGROUND: In Malawi, the national pneumococcal conjugate vaccine (PCV13) demonstrated less herd immunity than the USA, likely due to higher natural pneumococcal carriage rates. We assessed PCV13 efficacy against experimental pneumococcal carriage in healthy Malawian adults. We explored how natural carriage (pneumococcal carriage of any other serotype apart from 6B) influenced experimental carriage rates and vaccine efficacy. METHODS: Healthy adults aged 18-40 were randomly assigned PCV13 (n=98) or saline (n=106), followed by intranasal SPN 6B inoculation at 20,000 (n=40), 80,000 (n=74), or 160,000 (n=90) CFU/100µl, 28 days post-vaccination. We evaluated natural and experimental pneumococcal carriage before and after vaccination on days 2, 7, and 14 post-inoculation using culture and multiplex qPCR targeting lytA/cpsA genes and compared carriage rates by vaccination status. RESULTS: Of 204 participants, 19.6% (40) exhibited experimental carriage, detected by culture and 25.5% (52) by qPCR. Vaccinated individuals had lower experimental carriage rates (10.2%, n=10/98) compared to the placebo group (28.3%, n=30/106). This difference in vaccine efficacy was more pronounced in participants without natural carriage (PCV13=8% n=6/75 vs. placebo=25.9%, n=21/81) compared to those with natural carriage (PCV13=14.8%, n=4/27 vs. placebo=26.5%, n=9/34). Using a log-binomial model, vaccine effectiveness (VE) was 62%, whether assessed by culture or qPCR. Natural carriers had a lower VE of 52% compared to participants with no natural carriage (VE=69%). CONCLUSION: We have shown that PCV13 VE estimate (62%) is robust whether carriage is assessed by culture or qPCR. PCV13 had lower VE in natural carriers compared to those without natural carriage at the inoculation visit.

Incidence of Invasive and Noninvasive Pneumococcal Pneumonia Hospitalizations in People Aged ≥50 Years: Assessing Variability Across Denmark and Spain.

Determining pneumococcal pneumonia (PP) burden in the elderly population is challenging due to limited data on invasive PP (IPP) and, in particular, noninvasive PP (NIPP) incidence. Using retrospective cohorts of adults aged ≥50 years in Denmark (2 782 303) and the Valencia region, Spain (2 283 344), we found higher IPP hospitalization rates in Denmark than Valencia (18.3 vs 9/100 000 person-years [PY], respectively). Conversely, NIPP hospitalization rates were higher in Valencia (48.2 vs 7.2/100 000 PY). IPP and NIPP rates increased with age and comorbidities in both regions, with variations by sex and case characteristics (eg, complications, mortality). The burden of PP in adults is substantial, yet its true magnitude remains elusive. Discrepancies in clinical practices impede international comparisons; for instance, Valencia employed a higher frequency of urinary antigen tests compared to Denmark. Additionally, coding practices and prehospital antibiotic utilization may further influence these variations. These findings could guide policymakers and enhance the understanding of international disparities in disease burden assessments.

Clinical and Microbial Determinants of Upper Respiratory Colonization with Streptococcus pneumoniae and Native Microbiota in People with HIV-1 and Control Adults.

BACKGROUND: The substantial risk for respiratory and invasive infections with Streptococcus pneumoniae (Spn) among people with HIV-1 (PWH) begins with asymptomatic colonization. The frequency of Spn colonization among U.S. adults with and without HIV-1 infection is not well-characterized in the conjugate vaccine era. METHODS: We determined Spn colonization frequency by culture and specific lytA gene QPCR and microbiota profile by 16S rRNA gene sequencing in nasopharyngeal (NP) and oropharyngeal (OP) DNA from 138 PWH and 93 control adults and associated clinical characteristics. RESULTS: The frequencies of Spn colonization among PWH and controls did not differ (11.6% vs 8.6%, respectively; p=0.46) using combined results of culture and PCR, independent of vaccination or behavioral risks. PWH showed altered microbiota composition (i.e., beta-diversity. NP: p=0.0028, OP: p=0.0098), decreased alpha-diversity (NP: p=0.024, OP: p=0.0045), and differences in the relative abundance of multiple bacterial taxa. Spn colonization was associated with altered beta-diversity in the NP (p=0.011), but not OP (p=0.21). CONCLUSIONS: Despite widespread conjugate vaccine and antiretroviral use, frequencies of Spn colonization among PWH and controls are currently consistent with those reported in the pre-conjugate era. The persistently increased risk of pneumococcal disease despite ART may relate to behavioral and immunologic variables other than colonization.

Estimated population-level impact of pneumococcal conjugate vaccines against all-cause pneumonia mortality among unvaccinated age groups in five Latin American countries.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) provide strong direct protection in children, while limited data are available on their indirect effect on mortality among older age groups. This multi-country study aimed to assess the population-level impact of pediatric PCVs on all-cause pneumonia mortality among ≥5 years of age, and invasive pneumococcal disease (IPD) cases in Chile. METHODS: Demographic and mortality data from Argentina, Brazil, Chile, Colombia, and Mexico were collected considering the ≥ 5-year-old population, from 2000-2019, with 1,795,789 deaths due to all-cause pneumonia. IPD cases in Chile were also evaluated. Time series models were employed to evaluate changes in all-cause pneumonia deaths during the post-vaccination period, with other causes of death used as synthetic controls for unrelated temporal trends. RESULTS: No significant change in death rates due to all-cause pneumonia was detected following PCV introduction among most age groups and countries. The proportion of IPD cases caused by vaccine serotypes decreased from 29% (2012) to 6% (2022) among ≥65 years in Chile. DISCUSSION: While an effect of PCV against pneumonia deaths (a broad clinical definition that may not be specific enough to measure indirect effects) was not detected, evidence of indirect PCV impact was observed among vaccine-type-specific IPD cases.

The prostaglandin D2 antagonist asapiprant ameliorates clinical severity in young hosts infected with invasive Streptococcus pneumoniae.

Streptococcus pneumoniae (pneumococcus) remains a serious cause of pulmonary and systemic infections globally, and host-directed therapies are lacking. The aim of this study was to test the therapeutic efficacy of asapiprant, an inhibitor of prostaglandin D2 signaling, against pneumococcal infection. Treatment of young mice with asapiprant after pulmonary infection with invasive pneumococci significantly reduced systemic spread, disease severity, and host death. Protection was specific against bacterial dissemination from the lung to the blood but had no effect on pulmonary bacterial burden. Asapiprant-treated mice had enhanced antimicrobial activity in circulating neutrophils, elevated levels of reactive oxygen species (ROS) in lung macrophages/monocytes, and improved pulmonary barrier integrity indicated by significantly reduced diffusion of fluorescein isothiocyanate (FITC)-dextran from lungs into the circulation. These findings suggest that asapiprant protects the host against pneumococcal dissemination by enhancing the antimicrobial activity of immune cells and maintaining epithelial/endothelial barrier integrity in the lungs.

Prevalence, Clinical Severity, and Serotype Distribution of Pneumococcal Pneumonia Among Adults Hospitalized With Community-Acquired Pneumonia in Tennessee and Georgia, 2018-2022.

INTRODUCTION: Understanding the pneumococcal serotypes causing community-acquired pneumonia (CAP) is essential for evaluating the impact of pneumococcal vaccines. METHODS: We conducted a prospective surveillance study of adults aged ≥18 years hospitalized with CAP at 3 hospitals in Tennessee and Georgia between 1 September 2018 and 31 October 2022. We assessed for pneumococcal etiology with cultures, the BinaxNOW urinary antigen detection test, and serotype-specific urinary antigen detection assays that detect 30 pneumococcal serotypes contained in the investigational pneumococcal conjugate vaccine V116, as well as licensed vaccines PCV15 and PCV20 (except serotype 15B). The distribution of pneumococcal serotypes was calculated based on serotype-specific urinary antigen detection results. RESULTS: Among 2917 hospitalized adults enrolled with CAP, 352 (12.1%) patients had Streptococcus pneumoniae detected, including 51 (1.7%) patients with invasive pneumococcal pneumonia. The 8 most commonly detected serotypes were: 3, 22F, 19A, 35B, 9N, 19F, 23A, and 11A. Among 2917 adults with CAP, 272 (9.3%) had a serotype detected that is contained in V116, compared to 196 (6.7%) patients with a serotype contained in PCV20 (P < .001), and 168 (5.8%) patients with a serotype contained in PCV15 (P < .001). A serotype contained in V116 but not PCV15 or PCV20 was detected in 120 (4.1%) patients, representing 38.0% of serotype detections. CONCLUSIONS: Approximately 12% of adults hospitalized with CAP had S. pneumoniae detected, and approximately one-third of the detected pneumococcal serotypes were not contained in PCV15 or PCV20. Development of new pneumococcal vaccines with expanded serotype coverage has the potential to prevent a substantial burden of disease.

Age-Specific Resurgence in Invasive Pneumococcal Disease Incidence in the COVID-19 Pandemic Era and Its Association With Respiratory Virus and Pneumococcal Carriage Dynamics: A Time-Series Analysis.

Using multiple national surveillance systems, we found an increase in the incidence of invasive pneumococcal disease during after the relaxation of non-pharmaceutical interventions against COVID-19, which strongly varied by age. Age groups with higher incidence of respiratory syncytial virus and influenza also experienced higher increase in invasive pneumococcal disease incidence, with no change in pneumococcal carriage.

Pneumococcus and the stress-gradient hypothesis: A trade-off links R0 and susceptibility to co-colonization across countries.

Modern molecular technologies have revolutionized our understanding of bacterial epidemiology, but reported data across studies and different geographic endemic settings remain under-integrated in common theoretical frameworks. Pneumococcus serotype co-colonization, caused by the polymorphic bacteria Streptococcus pneumoniae, has been increasingly investigated and reported in recent years. While the global genomic diversity and serotype distribution of S. pneumoniae have been well-characterized, there is limited information on how co-colonization patterns vary globally, critical for understanding the evolution and transmission dynamics of the bacteria. Gathering a rich dataset of cross-sectional pneumococcal colonization studies in the literature, we quantified patterns of transmission intensity and co-colonization prevalence variation in children populations across 17 geographic locations. Linking these data to an SIS model with cocolonization under the assumption of quasi-neutrality among multiple interacting strains, our analysis reveals strong patterns of negative co-variation between transmission intensity (R0) and susceptibility to co-colonization (k). In line with expectations from the stress-gradient-hypothesis in ecology (SGH), pneumococcus serotypes appear to compete more in co-colonization in high-transmission settings and compete less in low-transmission settings, a trade-off which ultimately leads to a conserved ratio of single to co-colonization µ=1/(R0-1)k. From the mathematical model's behavior, such conservation suggests preservation of 'stability-diversity-complexity' regimes in coexistence of similar co-colonizing strains. We find no major differences in serotype compositions across studies, pointing to adaptation of the same set of serotypes across variable environments as an explanation for their differential interaction in different transmission settings. Our work highlights that the understanding of transmission patterns of Streptococcus pneumoniae from global scale epidemiological data can benefit from simple analytical approaches that account for quasi-neutrality among strains, co-colonization, as well as variable environmental adaptation.

Pneumococcus downregulates the molecular weight of the extracellular domain of the epidermal growth factor receptor of alveolar epithelial cells.

Pneumococcus is themajor cause of bacterial and invasive pneumococcal infections. Disrupting the alveolarepithelial barrier is an important step in the pathogenesis of invasivepneumococcal infections. The epidermal growth factor receptor (EGFR) maintainsthe integrity of the alveolar epithelial barrier. In this study, we showed that secretory pneumococcal molecules decrease the molecular weight of EGFR without peptide degradation and inhibit alveolar epithelial cell proliferation via EGFR.

Activating A1 adenosine receptor signaling boosts early pulmonary neutrophil recruitment in aged mice in response to Streptococcus pneumoniae infection.

BACKGROUND: Streptococcus pneumoniae (pneumococcus) is a leading cause of pneumonia in older adults. Successful control of pneumococci requires robust pulmonary neutrophil influx early in infection. However, aging is associated with aberrant neutrophil recruitment and the mechanisms behind that are not understood. Here we explored how neutrophil recruitment following pneumococcal infection changes with age and the host pathways regulating this. RESULTS: Following pneumococcal infection there was a significant delay in early neutrophil recruitment to the lungs of aged mice. Neutrophils from aged mice showed defects in trans-endothelial migration in vitro compared to young controls. To understand the pathways involved, we examined immune modulatory extracellular adenosine (EAD) signaling, that is activated upon cellular damage. Signaling through the lower affinity A2A and A2B adenosine receptors had no effect on neutrophil recruitment to infected lungs. In contrast, inhibition of the high affinity A1 receptor in young mice blunted neutrophil recruitment to the lungs following infection. A1 receptor inhibition decreased expression of CXCR2 on circulating neutrophils, which is required for trans-endothelial migration. Indeed, A1 receptor signaling on neutrophils was required for their ability to migrate across endothelial cells in response to infection. Aging was not associated with defects in EAD production or receptor expression on neutrophils. However, agonism of A1 receptor in aged mice rescued the early defect in neutrophil migration to the lungs and improved control of bacterial burden. CONCLUSIONS: This study suggests age-driven defects in EAD damage signaling can be targeted to rescue the delay in pulmonary neutrophil migration in response to bacterial pneumonia.

Prior pneumococcal vaccination improves in-hospital mortality among elderly population hospitalized due to community-acquired pneumonia.

BACKGROUND: Pneumococcal vaccination is a preventive method to reduce pneumonia related mortality. However, real-world data on efficacy of the pneumococcal vaccine in reducing mortality is lacking, especially in elderly patients. This study was conducted to assess the effects of prior pneumococcal vaccination in elderly pneumonia patients. METHODS: The data was procured from the Health Insurance Review and Assessment and Quality Assessment database. Hospitalized patients who met the criteria of community-acquired pneumonia (CAP) were included and they were grouped according to vaccination state. Patients were aged ≥ 65 years and treated with beta-lactam, quinolone, or macrolide. Patients were excluded when treatment outcomes were unknown. RESULTS: A total of 4515 patients were evaluated, and 1609 (35.6%) of them were vaccinated prior to hospitalization. Mean age was 77.0 [71.0;82.0], 54.2% of them were male, and mean Charlson comorbidity index (CCI) was 3.0. The patients in the vaccinated group were younger than those in the unvaccinated group (76.0 vs. 78.0 years; P < 0.001), and showed higher in-hospital improvement (97.6 vs. 95.0%; P < 0.001) and lower 30-day mortality (2.6 vs. 5.3%; P < 0.001). After adjusting confounding factors such as age, gender, CURB score and CCI score, the vaccinated group demonstrated a significant reduction in 30-day mortality (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.41-0.81; P < 0.01) and in-hospital mortality (HR 0.53, 95% CI0.37-0.78; P < 0.001) compared to the unvaccinated group in multivariate analysis. Vaccinated group showed better 30-day survival than those in non-vaccinated group (log-rank test < 0.05). CONCLUSIONS: Among elderly hospitalized CAP patients, prior pneumococcal vaccination was associated with improved in-hospital mortality and 30-day mortality.

The Microbial Etiology of Community-Acquired Pneumonia in Adults: from Classical Bacteriology to Host Transcriptional Signatures.

All modern advances notwithstanding, pneumonia remains a common infection with substantial morbidity and mortality. Understanding of the etiology of pneumonia continues to evolve as new techniques enable identification of already known organisms and as new organisms emerge. We now review the etiology of pneumonia (at present often called "community-acquired pneumonia") beginning with classic bacteriologic techniques, which identified Streptococcus pneumoniae as the overwhelmingly common cause, to more modern bacteriologic studies, which emphasize Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Enterobacteriaceae, Pseudomonas, and normal respiratory flora. Urine antigen detection is useful in identifying Legionella and pneumococcus. The low yield of bacteria in recent studies is due to the failure to obtain valid sputum samples before antibiotics are administered. The use of high-quality sputum specimens enables identification of recognized ("typical") bacterial pathogens as well as a role for commensal bacteria ("normal respiratory flora"). Nucleic acid amplification technology for viruses has revolutionized diagnosis, showing the importance of viral pneumonia leading to hospitalization with or without coinfecting bacterial organisms. Quantitative PCR study of sputum is in its early stages of application, but regular detection of high counts of bacterial DNA from organisms that are not seen on Gram stain or grown in quantitative culture presents a therapeutic dilemma. This finding may reflect the host microbiome of the respiratory tract, in which case treatment may not need to be given for them. Finally, host transcriptional signatures might enable clinicians to distinguish between viral and bacterial pneumonia, an important practical consideration.

[Vaccination status and factors associated with pneumococcal vaccination in geriatric short-stay care]. / Statut vaccinal et facteurs associés à la vaccination antipneumococcique en court séjour gériatrique.

Nearly two-thirds of geriatric short-stay patients were eligible for pneumococcal vaccination. Among patients eligible for vaccination, less than 5 % had received at least one injection of pneumococcal vaccine on admission. We found no modifiable factors associated with vaccination status, but several avenues for improving vaccination coverage.

Association of Upper Respiratory Streptococcus pneumoniae Colonization With Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Adults.

BACKGROUND: Streptococcus pneumoniae interacts with numerous viral respiratory pathogens in the upper airway. It is unclear whether similar interactions occur with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We collected saliva specimens from working-age adults undergoing SARS-CoV-2 molecular testing at outpatient clinics and via mobile community-outreach testing between July and November 2020 in Monterey County, California. After bacterial culture enrichment, we tested for pneumococci by means of quantitative polymerase chain reaction targeting the lytA and piaB genes, and we measured associations with SARS-CoV-2 infection using conditional logistic regression. RESULTS: Analyses included 1278 participants, with 564 enrolled in clinics and 714 enrolled through outreach-based testing. The prevalence of pneumococcal carriage was 9.2% (117 of 1278) among all participants (11.2% [63 of 564] in clinic-based testing and 7.6% [54 of 714] in outreach-based testing). The prevalence of SARS-CoV-2 infection was 27.4% (32 of 117) among pneumococcal carriers and 9.6% (112 of 1161) among noncarriers (adjusted odds ratio [aOR], 2.73 [95% confidence interval (CI): 1.58-4.69). Associations between SARS-CoV-2 infection and pneumococcal carriage were enhanced in the clinic-based sample (aOR, 4.01 [95% CI: 2.08-7.75]) and among symptomatic participants (3.38 [1.35-8.40]), compared with findings within the outreach-based sample and among asymptomatic participants. The adjusted odds of SARS-CoV-2 coinfection increased 1.24-fold (95% CI: 1.00-1.55-fold) for each 1-unit decrease in piaB quantitative polymerase chain reaction cycle threshold value among pneumococcal carriers. Finally, pneumococcal carriage modified the association of SARS-CoV-2 infection with recent exposure to a suspected coronavirus disease 2019 case (aOR, 7.64 [95% CI: 1.91-30.7] and 3.29 [1.94-5.59]) among pneumococcal carriers and noncarriers, respectively). CONCLUSIONS: Associations of pneumococcal carriage detection and density with SARS-CoV-2 suggest a synergistic relationship in the upper airway. Longitudinal studies are needed to determine interaction mechanisms between pneumococci and SARS-CoV-2.

Immunological Efficacy of Pneumococcal Vaccination Including the 13-Valent Pneumococcal Conjugate Vaccine in Adult Patients With Sickle Cell Disease: Results of the Randomized DREVAC Controlled Trial.

BACKGROUND: Patients with sickle cell disease (SCD) are at high risk for invasive pneumococcal diseases. The immunological efficacy of 13-valent conjugate pneumococcal vaccine (PCV13) followed by a 23-valent polysaccharide vaccine (PPSV23) is poorly documented in adults with SCD. METHODS: This was a randomized open-labeled phase 2 study of the immunogenicity of PCV13 at week 0, followed by PPSV23 at week 4, compared with PPSV23 alone at week 4 in adult patients with SCD. The proportion of responders (4-fold increase in serotype-specific immunoglobulin [Ig] G antibodies) to ≥10 shared serotypes was assessed at week 8. Secondary end points were (1) geometric mean titers, (2) responders to 0-1, 2-5, 6-9, or 10-12 serotypes, (3) pneumococcal opsonophagocytic activity, and (4) response durability at weeks 24 and 96. RESULTS: In total, 128 patients were randomized in the PCV13/PPSV23 (n = 63) or PPSV23-alone groups (n = 65). At week 8, 24.56% and 8.20% of patients from the PCV13/PPSV23 and PPSV23 groups, respectively, reached the primary end point (P = .02). These numbers were 36.2% and 8.7% for opsonophagocytic activity responders (P = .002). A combined PCV13/PPSV23 strategy improved the breadth of responses to 0-1, 2-5, 6-9, or 10-12 serotypes with 15.8%, 35%, 24.6%, and 24.6% versus 52.5%, 31%, 8%, and 8% in the PPSV23 group. At week 96, geometric mean titers were significantly higher in the PCV13/PPSV23 than in the PPSV23-alone group for 5 serotypes (4, 14, 19A, 19F, 23F). CONCLUSIONS: A PCV13/PPSV23 regimen improved the breadth and magnitude of antibody responses against a large range of pneumococcal serotypes in adults with SCD. The sustainability of the immune response requires recall strategies.Clinical Trial Registration: NCT02274415.

Unmasking Pneumococcal Carriage in a High Human Immunodeficiency Virus (HIV) Prevalence Population in two Community Cohorts in South Africa, 2016-2018: The PHIRST Study.

BACKGROUND: Longitudinal pneumococcus colonization data in high human immunodeficiency virus (HIV) prevalence settings following pneumococcal conjugate vaccine introduction are limited. METHODS: In 327 randomly selected households, 1684 individuals were enrolled and followed-up for 6 to 10 months during 2016 through 2018 from 2 communities. Nasopharyngeal swabs were collected twice weekly and tested for pneumococcus using quantitative lytA real-time polymerase chain reaction. A Markov model was fitted to the data to define the start and end of an episode of colonization. We assessed factors associated with colonization using logistic regression. RESULTS: During the study period, 98% (1655/1684) of participants were colonized with pneumococcus at least once. Younger age (<5 years: adjusted odds ratio [aOR], 14.1; 95% confidence [CI], 1.8-111.3, and 5-24 years: aOR, 4.8, 95% CI, 1.9-11.9, compared with 25-44 years) and HIV infection (aOR, 10.1; 95% CI, 1.3-77.1) were associated with increased odds of colonization. Children aged <5 years had fewer colonization episodes (median, 9) than individuals ≥5 years (median, 18; P < .001) but had a longer episode duration (<5 years: 35.5 days; interquartile range, 17-88) vs. ≥5 years: 5.5 days (4-12). High pneumococcal loads were associated with age (<1 year: aOR 25.4; 95% CI, 7.4-87.6; 1-4 years: aOR 13.5, 95% CI 8.3-22.9; 5-14 years: aOR 3.1, 95% CI, 2.1-4.4 vs. 45-65 year old patients) and HIV infection (aOR 1.7; 95% CI 1.2-2.4). CONCLUSIONS: We observed high levels of pneumococcus colonization across all age groups. Children and people with HIV were more likely to be colonized and had higher pneumococcal loads. Carriage duration decreased with age highlighting that children remain important in pneumococcal transmission.

Inducible Mega-Mediated Macrolide Resistance Confers Heteroresistance in Streptococcus pneumoniae.

In Streptococcus pneumoniae (Spn), the 5.4 to 5.5 kb Macrolide Genetic Assembly (Mega) encodes an efflux pump (Mef[E]) and a ribosomal protection protein (Mel) conferring antibiotic resistance to commonly used macrolides in clinical isolates. We found the macrolide-inducible Mega operon provides heteroresistance (more than 8-fold range in MICs) to 14- and 15-membered ring macrolides. Heteroresistance is commonly missed during traditional clinical resistance screens but is highly concerning as resistant subpopulations can persist despite treatment. Spn strains containing the Mega element were screened via Etesting and population analysis profiling (PAP). All Mega-containing Spn strains screened displayed heteroresistance by PAP. The heteroresistance phenotype was linked to the mRNA expression of the mef(E)/mel operon of the Mega element. Macrolide induction uniformly increased Mega operon mRNA expression across the population, and heteroresistance was eliminated. A deletion of the 5' regulatory region of the Mega operon results in a mutant deficient in induction as well as in heteroresistance. The mef(E)L leader peptide sequence of the 5' regulatory region was required for induction and heteroresistance. Treatment with a noninducing 16-membered ring macrolide antibiotic did not induce the mef(E)/mel operon or eliminate the heteroresistance phenotype. Thus, inducibility of the Mega element by 14- and 15-membered macrolides and heteroresistance are linked in Spn. The stochastic variation in mef(E)/mel expression in a Spn population containing Mega provides the basis for heteroresistance.

Pneumococcal Vaccines: Host Interactions, Population Dynamics, and Design Principles.

Streptococcus pneumoniae (the pneumococcus) is a nasopharyngeal commensal and respiratory pathogen. Most isolates express a capsule, the species-wide diversity of which has been immunologically classified into ∼100 serotypes. Capsule polysaccharides have been combined into multivalent vaccines widely used in adults, but the T cell independence of the antibody response means they are not protective in infants. Polysaccharide conjugate vaccines (PCVs) trigger a T cell-dependent response through attaching a carrier protein to capsular polysaccharides. The immune response stimulated by PCVs in infants inhibits carriage of vaccine serotypes (VTs), resulting in population-wide herd immunity. These were replaced in carriage by non-VTs. Nevertheless, PCVs drove reductions in infant pneumococcal disease, due to the lower mean invasiveness of the postvaccination bacterial population; age-varying serotype invasiveness resulted in a smaller reduction in adult disease. Alternative vaccines being tested in trials are designed to provide species-wide protection through stimulating innate and cellular immune responses, alongside antibodies to conserved antigens.

Effect of Haemophilus influenzae, Streptococcus pneumoniae and influenza vaccinations on infections, immune response and asthma control in preschool children with asthma.

BACKGROUND: Haemophilus influenzae (H. influenzae), Streptococcus pneumoniae (pneumococcus) and influenza vaccines are administered in children to prevent infections caused by these pathogens. The benefits of vaccination for asthma control in children and the elicited immune response are not fully understood. This study aimed to investigate the impact of these vaccinations on respiratory infections, asthma symptoms, asthma severity and control status, pathogen colonization and in vitro immune responses to different stimulants mimicking infections in asthmatic children. METHODS: Children aged 4-6 years were recruited into the multicentre prospective PreDicta study conducted across five European countries. Information about vaccination history, infections, antibiotic use, inhaled corticosteroid (ICS) use and asthma symptoms in the last 12 months were obtained from questionnaires of the study. Nasopharyngeal samples were collected at the first visit to assess bacterial and viral colonization, and venous blood for isolation of peripheral blood mononuclear cells (PBMCs). The PBMCs were stimulated with phytohemagglutinin, R848, Poly I:C and zymosan. The levels of 22 cytokines and chemokines were measured in cell culture supernatants using a luminometric multiplex assay. RESULTS: One-hundred and forty asthmatic preschool children (5.3 ± 0.7 years) and 53 healthy children (5.0 ± 0.8 years) from the PreDicta cohort were included in the current study. Asthmatic children were associated with more frequent upper and lower respiratory infections, and more frequent and longer duration of antibiotic use compared with healthy children. In asthmatic children, sufficient H. influenzae vaccination was associated with a shorter duration of upper respiratory infection (URI) and overall use and average dose of ICS. The airway colonization was characterized by less pneumococcus and more rhinovirus. Pneumococcal vaccination was associated with a reduction in the use rate and average dose of ICS, improved asthma control, and less human enterovirus and more H. influenzae and rhinovirus (RV) airway colonization. Influenza vaccination in the last 12 months was associated with a longer duration of URI, but with a decrease in the occurrence of lower respiratory infection (LRI) and the duration of gastrointestinal (GI) infection and antibiotic use. Asthmatic preschoolers vaccinated with H. influenzae, pneumococcus or influenza presented higher levels of Th1-, Th2-, Th17- and regulatory T cells (Treg)-related cytokines in unstimulated PBMCs. Under stimulation, PBMCs from asthmatic preschoolers with pneumococcal vaccination displayed a predominant anti-inflammatory immune response, whereas PBMCs from asthmatic children with sufficient H. influenzae or influenza vaccination were associated with both pro- and anti-inflammatory immune responses. CONCLUSION: In asthmatic preschoolers, the standard childhood vaccinations to common respiratory pathogens have beneficial effects on asthma control and may modulate immune responses relevant to asthma pathogenesis.

Invasiveness potential of pneumococcal serotypes in children after introduction of PCV13 in Blantyre, Malawi.

INTRODUCTION: The introduction of PCV13 to the Malawi infant immunization schedule in 2011 has been associated with reduced disease from Streptococcus pneumoniae. Improved understanding of serotypes with high invasive potential can guide future vaccination interventions. We aimed to estimate pneumococcal serotypes associated with acute respiratory infection (ARI) and invasive pneumococcal disease (IPD) in hospitalized children in Blantyre, Malawi. METHODS: We analysed data from healthy children under 5 years in the community in Blantyre and children admitted to Queen Elizabeth Central Hospital with ARI between 2015 and 2018. Nasopharyngeal swabs from children were tested for S. pneumoniae and serotyped by latex agglutination if positive. We analysed culture-positive blood and cerebrospinal fluid samples from admitted children between 2012 and 2018 to identify cases of IPD after the introduction of PCV13. We calculated the age-adjusted odds ratio (OR) of carriage for S. pneumoniae vaccine serotypes (VT) comparing those with ARI to healthy children. We also calculated age-adjusted ORs comparing serotypes causing IPD to carriage in the community with OR > 1 indicating high invasive potential. RESULTS: Serotypes 5 (OR 24.73 [95% CI 7.90-78.56] p < 0.001), 1 (OR 23.38 [95% CI 9.75-56.06] p < 0.001), and 6B (OR 4.73 [95% CI 1.66-11.64] p = 0.001) had high invasive potential. Serotype 6B was no longer significant (OR 1.34 [95% CI 0.07-6.87] p = 0.777) in a sensitivity analysis accounting for year of recruitment. The prevalence of S. pneumoniae carriage in the community was 72.6% [95% CI 71.3-74.0] (3078/4238) and 23.4% (719/3078) of positive community samples were VT. The carriage prevalence in those hospitalised with ARI was 45.5% [95% CI 42.1-48.9] (389/855) and 43.8% of hospital attendees reported antibiotic use prior to admission. We did not identify significant associations with carriage of any serotypes in those with ARI. CONCLUSIONS: Pneumococcal serotypes 5 and 1 are associated with high invasive potential. Despite high community pneumococcal carriage, pre-hospital antibiotic usage likely reduces pneumococcal detection among children admitted in this setting and further research is needed to investigate serotypes associated with ARI. Data from this study can guide future preventative vaccination strategies in Malawi.