Incidence and Estimated Vaccine Effectiveness Against Hospitalizations for All-Cause Pneumonia Among Older US Adults Who Were Vaccinated and Not Vaccinated With 13-Valent Pneumococcal Conjugate Vaccine.

Importance: Following routine use of 13-valent pneumococcal conjugate vaccine (PCV13) in children in 2010, invasive pneumococcal disease rates have decreased substantially in children and adults. In 2014, the Advisory Committee for Immunization Practices recommended routine use of PCV13 among adults aged 65 years or older; previously only 23-valent pneumococcal polysaccharide vaccine (PPV23) was recommended. Objective: To estimate the association between the incidence of hospitalized all-cause pneumonia and lower respiratory tract infections (LRTI) and PCV13 vaccination among older adults at Kaiser Permanente Northern California (KPNC). Design, Setting, and Participants: This retrospective cohort study included adults at KPNC aged 65 years or older between July 1, 2015, and June 30, 2018, born after 1936 with no known history of PPV23 or PCV13 receipt before age 65. The study took place at an integrated health care system with an annual membership more than 4 million individuals, approximately 15% of whom are 65 years or older and broadly representative of the region. Data analysis took place from July 2018 to December 2021, and data collection took place from November 2016 to June 2018. Exposures: PCV13 vaccination status was ascertained from the electronic medical record (EMR). Individuals were considered vaccinated 14 days following immunization. Main Outcomes and Measures: First hospitalized all-cause pneumonia was identified in the EMR using primary/secondary discharge diagnosis International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. First hospitalized LRTI was identified using pneumonia codes and acute bronchitis codes. Relative risk (RR) of first pneumonia or LRTI hospitalization of individuals who were PCV13 vaccinated vs PCV13 unvaccinated was estimated using Poisson regressions adjusted for sex, race, ethnicity, age, influenza vaccine receipt, PPV23 receipt since age 65, pneumonia risk factors, health care use, and season. Vaccine effectiveness (VE) was estimated as (1-RR) × 100%. Results: Of 192 061 adults, 107 957 (56%) were female and 139 024 (72%) were White individuals. PCV13 coverage increased from 0 in 2014 to 135 608 (76.9%) by 2018. There were 3488 individuals with 3766 pneumonia hospitalizations and 3846 individuals with 4173 LRTI hospitalizations. PCV13 was associated with an adjusted VE of 10.0% (95% CI, 2.4-17.0; P = .01) against hospitalized pneumonia and 9.4% (95% CI, 2.1-16.1; P = .01) against hospitalized LRTI. Conclusions and Relevance: In the context of a robust pediatric PCV13 immunization program, PCV13 vaccination of adults aged 65 years or older was associated with significant reductions in hospitalizations for all-cause pneumonia and LRTI. Vaccinating older adults with PCVs may provide broader public health benefit against pneumonia hospitalizations.

Protective effects of Re-yan-ning mixture on Streptococcus pneumonia in rats based on network pharmacology.

CONTEXT: Re-yan-ning mixture (RYNM) is a new national drug approved by China's State Food and Drug Administration for the treatment of colds, simple pneumonia and acute bronchitis. OBJECTIVE: To determine the mechanism of action of RYNM in the treatment of bacterial pneumonia. MATERIALS AND METHODS: Using the network pharmacology approach, the multiple components, component candidate targets and multiple therapeutic targets of RYNM were screened and functionally enriched. Also, we established a rat Streptococcus pneumonia model to verify the results of network pharmacology enrichment analysis. Forty male SPF Sprague Dawley rats were divided into four groups of 10 rats: control (normal saline), model (normal saline), levofloxacin-intervened and RYNM-intervened groups. IL-10, NOS2, COX-1, IL-6, TNF-α and NF-κB in serum and BALF were detected by ELISA. Western blot detected IL-17, IL-6, TNF-α, COX-2 and Bcl-2. RESULTS: The network pharmacology approach successfully identified 48 bioactive components in RYNM, and 65 potential targets and 138 signal pathways involved in the treatment of Streptococcus pneumonia with RYNM. The in vivo experiments indicated that model group has visible inflammation and lesions while RYNM and levofloxacin groups have not. The RYNM exhibited its therapeutic effects on Streptococcus pneumonia mainly via the regulation of cell proliferation and survival through the IL-6/IL-10/IL-17, Bax/Bcl-2, COX-1/COX-2, NF-κB and TNF-α signalling pathways. DISCUSSION AND CONCLUSIONS: The present study demonstrated the protective effects of RYNM on Streptococcus pneumonia, providing a potential mechanism for the treatment of bacterial pneumonia with RYNM.

Cost-Effectiveness of Pneumococcal Vaccination Policies and Uptake Programs in US Older Populations.

BACKGROUND/OBJECTIVES: Recently revised vaccination recommendations for US adults, aged 65 years and older, include both 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13), with PCV13 now recommended for immunocompetent older people based on shared decision making. The public health impact and cost-effectiveness of this recommendation or of pneumococcal vaccine uptake improvement interventions are unclear. DESIGN: Markov decision analysis. SETTING AND PARTICIPANTS: Hypothetical 65-year-old general and black population cohorts. INTERVENTION: Current pneumococcal vaccination recommendations for US older people, an alternative policy omitting PCV13 in immunocompetent older people, and vaccine uptake improvement programs. RESULTS: The current pneumococcal vaccination recommendation was the most effective strategy, but afforded slight public health benefits compared to an alternative (PPSV23 for all older people plus PCV13 for the immunocompromised) and cost greater than $750 000 per quality-adjusted life-year (QALY) gained in either population group with a vaccine uptake improvement program (absolute uptake increase = 12.3%; cost = $1.78/eligible patient) in place. The alternative strategy was more economically favorable, but cost greater than $100 000/QALY in either population, with or without an uptake intervention. Results were robust in sensitivity analyses; however, in black older people, the alternative strategy with an uptake program was most likely to be favored in probabilistic sensitivity analyses at a $150 000/QALY gained threshold. CONCLUSION: Current pneumococcal vaccination recommendations for US older people are economically unfavorable compared to an alternative strategy omitting PCV13 in the immunocompetent. The alternative recommendation with an uptake improvement program may be economically reasonable in black population analyses and could be worth considering as a population-wide recommendation if mitigating racial disparities is a priority. J Am Geriatr Soc 68:1271-1278, 2020.

Phenotypic and genotypic characterization of serogroup 6 Streptococcus pneumoniae isolates collected during 10-valent pneumococcal conjugate vaccine era in Bulgaria.

Serogroup 6 remains common in the pneumococcal-conjugated vaccine era in Bulgaria; therefore, we investigated its clonal and serotype dynamics. The antibiotic susceptibilities were assessed by broth microdilution. Strains identified as serogroup 6 with latex agglutination method were subjected to serotype-specific PCRs. Erythromycin-resistant strains were analyzed by PCR for presence of ermB and mefE genes. MLST was performed to define clonal composition of the sequence types (STs). Serogroup 6 was represented by 40 (13.3%) from 301 invasive and non-invasive Streptococcus pneumoniae isolates. Molecular serotyping revealed new emerging serotype 6C (6.6%), not detected in pre-vaccine era. Among unvaccinated patients, mostly we observed serotypes 6А (57.1%) and 6В (28.6%). Serotype 6C was distinctive for vaccinated children (64%), followed by 6A (24%). Penicillin and ceftriaxone non-susceptible serogroup 6 strains were 65% and 5%, respectively; erythromycin- and clindamycin-resistant were 70.0% and 52.5%, respectively. Multidrug-resistant strains were 57.5%. Prevalent genetic determinant for macrolide resistance was ermB gene (75%). MLST revealed 17 STs into 5 clonal complexes and 7 singletons. Predominant genetic lineage was CC386, represented by MDR-6C non-invasive strains. Serotype 6B, principally responsible for invasive diseases in the pre-vaccine era, retreated this position to serotype 6A.

Effect of atorvastatin on humoral immune response to 23-valent pneumococcal polysaccharide vaccination in healthy volunteers: The StatVax randomized clinical trial.

BACKGROUND: The immunomodulatory effects of statins on vaccine response remain uncertain. Therefore, the objective of this study was to determine if atorvastatin enhances pneumococcal-specific antibody titer following 23-valent pneumococcal polysaccharide vaccination. METHODS: Double-blind, placebo-controlled, single-center randomized clinical trial entitled StatVax. Subjects were enrolled between June and July 2014 and followed up through September 2014. 33 healthy volunteers signed informed consent after volunteer sampling. 11 participants were excluded; 22 healthy volunteers without prior pneumococcal vaccination were enrolled and completed the study. Participants were randomized to receive a 28-day course of 40 mg atorvastatin (n = 12) or matching lactose placebo (n = 10). On day 7 of treatment, Pneumovax 23 was administered intramuscularly. The primary outcome was fold change in total pneumococcal-specific antibody titer determined by a ratio of post-vaccination titer over baseline titer. Secondary outcomes included serotype-specific pneumococcal antibody titer, seroconversion, complete blood counts (CBC), erythrocyte sedimentation rate (ESR), and serum cytokine analysis. RESULTS: Of the 22 randomized patients (mean age, 23.86; SD, 4.121; 11 women [50%]), 22 completed the trial. Total anti-pneumococcal antibody titer in the atorvastatin group went from a baseline mean of 32.58 (SD, 15.96) to 147.7 (SD, 71.52) µg/mL at 21 days post-vaccination while titer in the placebo group went from a mean of 30.81 (SD, 13.04) to 104.4 (SD, 45) µg/mL. When comparing fold change between treatment groups, there was a significant increase in fold change of total anti-pneumococcal antibody titer in the atorvastatin group compared to the placebo group (2-way ANOVA, p = .0177). CONCLUSIONS: Atorvastatin enhances antigen-specific primary humoral immune response to a T cell-independent pneumonia vaccination. Pending confirmation by larger cohort studies of target populations, peri-vaccination conventional doses of statins can become a novel adjuvant for poorly-immunogenic polysaccharide-based vaccines. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02097589.

The impact of pneumococcal vaccine in reducing pneumonia hospitalizations in children under 5 years old, in Santa Catarina, Brazil, 2006 a 2014. / Impacto da vacina pneumocócica na redução das internações hospitalares por pneumonia em crianças menores de 5 anos, em Santa Catarina, 2006 a 2014.

OBJECTIVE: to analyze the impact of pneumococcal conjugate vaccine (PCV10) on pneumonia hospital admissions among children in Santa Catarina, Brazil, 2006-2014. METHODS: this was an ecological study using data obtained from Brazilian National Health System Information Technology Department (Datasus) for 2006-2009 (pre-vaccination period) and 2010-2014 (post-vaccination period); time trends were evaluated using the Poisson regression coefficient. RESULTS: in the comparison between pre- and post-vaccination periods, the percentage difference in the hospitalization rate for children under 1 year old ranged from -44.1% in the Western region to -1.4% in the Serrano Plateau region, and in children between 1-4 years old it ranged from -37.1% in the Northern Plateau region to 16.9% in the Serrano Plateau region (p<0.05); hospitalization rates in the state reduced by 23.3% in children under 1 year old and by 8.4% in those aged 1-4 years. CONCLUSION: a significant reduction in the rate of pneumonia hospitalization in children under 1 year old age was found, suggesting the effectiveness of the vaccine in reducing hospitalizations.

Cost-effectiveness analysis of 13-valent pneumococcal conjugate vaccine versus 23-valent pneumococcal polysaccharide vaccine in an adult population in South Korea.

In South Korea, the National Immunization Program offers a 23-valent pneumococcal polysaccharide vaccine (PPSV23) for the elderly; however, the 13-valent pneumococcal conjugate vaccine (PCV13) is not included, and vaccination is not offered to younger, at-risk populations. This study offers a comparative analysis of PCV13 and PPSV23 in Korea's adults, stratified by age and risk group. A Markov model with a lifetime horizon was developed from the healthcare perspective. Data sources included the Health Insurance Review & Assessment Service, Korea Centre for Disease Control & Prevention and Korean medical institutions. An expert panel tested data validity. The CAPiTA trial and Cochrane meta-analysis were used to obtain vaccine effectiveness data. Regardless of co-morbidity, when the sequential PCV13-PPSV23 strategy was compared to that using PPSV23-only, in elderly populations, the incremental cost-effectiveness ratio (ICER) was 3,300 USD per quality-adjusted life years (QALY). For the risk group aged ≥65 years, the ICER of the addition of PCV13 over the existing PPSV23-only strategy was 3,404 USD/QALY. However, on replacing PPSV23 with PCV13, for all elderly populations, an ICER of 1,421 USD/QALY resulted; for the risk group aged ≥65 years, the ICER was 1,736 USD/QALY. For the 18-64 year-old risk group, the sequential PCV13-PPSV23 strategy yielded an ICER of 3,629 USD/QALY over the PPSV23-only strategy, and 6,643 USD/QALY compared to no vaccination. Thus, the PCV13→PPSV23 combination strategy for elderly populations was found to be a cost-effective alternative to the current National Immunization Program regardless of co-morbidity. This finding was the same as that for younger, at-risk populations.

Vaccination coverage and use of the Brazilian Health System for vaccination against influenza and pneumonia in adults and elderly with self-reported diabetes, municipality of São Paulo, 2003, 2008 and 2015. / Cobertura vacinal e utilização do SUS para vacinação contra gripe e pneumonia em adultos e idosos com diabetes autorreferida, no município de São Paulo, 2003, 2008 e 2015.

OBJECTIVE: to estimate the vaccination coverage against influenza and pneumonia and to analyze the utilization of Brazilian National Health System-SUS for vaccination in adults and elderly with self-reported diabetes in São Paulo, Brazil, in 2003, 2008 and 2015. METHODS: Cross-sectional studies with data from the ISA-Capital (population-based household surveys). RESULTS: 3,357, 3,271 and 4,043 were interviewed in 2003, 2008 and 2015; the prevalence of diabetes mellitus were 5.0% (2003), 6.4% (2008) and 7.7% (2015); fewer than half of people with diabetes, vaccinated against influenza (47.2%) and pneumonia (17.9%) in 2003, with a small increase in 2015 (59.2% and 26.1%, respectively); the majority of people who are vaccinated against influenza and pneumonia used SUS, 88.7% (2003) and 97.2% (2015) for influenza; 84.7% (2003) and 94.5% (2015) for pneumonia, without difference among age, sex, education level and ethnicity. CONCLUSION: despite the low vaccination coverage against influenza and pneumonia in the population with diabetes mellitus since 2003 the utilization of SUS to vaccination has been progressively expanding.

Immunogenicity differences of a 15-valent pneumococcal polysaccharide conjugate vaccine (PCV15) based on vaccine dose, route of immunization and mouse strain.

Pneumococcal disease continues to be a medical need even with very effective vaccines on the market. Globally, there are extensive research efforts to improve serotype coverage with novel vaccines; therefore, conducting preclinical studies in different animal models becomes essential. The work presented herein focuses on evaluating a 15-valent pneumococcal conjugate vaccine (PCV15) in mice. Initially we evaluated several doses of PCV15 in Balb/c mice. The optimal vaccine dose was determined to be 0.4µg per pneumococcal polysaccharide (PS) (0.8µg of 6B) for subsequent studies. This PS dose was chosen for PCV evaluation in mice based on antibody levels determined by multiplexed electrochemiluminescent (ECL) assays, T-cell responses following in vitro stimulation with CRM197 peptides and protection from pneumococcal challenge. We then selected four mouse strains for evaluation: Balb/c, C3H/HeN, CD1 and Swiss Webster (SW), immunized with PCV15 by either intraperitoneal (IP) or intramuscular (IM) routes. We assessed IgG responses by ECL assays and functional antibody activity by multiplexed opsonophagocytic assays (MOPA). Every mouse strain evaluated responded to all 15 serotypes contained in the vaccine. Mice tended to have lower responses to serotypes 6B, 23F and 33F. The IP route of immunization resulted in higher antibody titers for most serotypes in Balb/c, C3H and SW. CD1 mice tended to respond similarly for most serotypes, regardless of route of immunization. Similar trends were observed with the four mouse strains when evaluating functional antibody activity. Given the differences in antibody responses based on mouse strain and route of immunization, it is critical to evaluate pneumococcal vaccines in multiple animal models to determine the optimal formulation before moving to clinical trials.

Respiratory Conditions Update: Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is defined as persistent airflow limitation due to irritant-induced chronic inflammation. A postbronchodilator forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio of 0.7 or less is diagnostic in a patient with dyspnea, chronic cough or sputum production, and a history of irritant exposure. Tobacco smoking is the most significant etiology, and smoking cessation is the only intervention shown to slow disease progression. Long-acting beta2-agonists and long-acting muscarinic antagonists are first-line treatments for patients with persistently symptomatic COPD with an FEV1 of 80% or less of predicted. When COPD is uncontrolled with a long-acting bronchodilator, combination therapy with a long-acting muscarinic antagonist-long-acting beta2-agonist or long-acting beta2-agonist-inhaled corticosteroid should be prescribed. Patients with COPD and reduced exercise tolerance should undergo pulmonary rehabilitation and be evaluated for supplemental oxygen therapy. Other treatment options for persistently symptomatic COPD include inhaler triple therapy (ie, long-acting muscarinic antagonist, long-acting beta2-agonist, inhaled corticosteroid), phosphodiesterase type 4 inhibitors, oxygen, and surgical interventions.

Respiratory Conditions Update: Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal recessive genetic disease that occurs in approximately 1 in 2,500 white live births. It is less common in nonwhite individuals. A dysfunctional epithelial chloride channel leads to excessively thick mucus affecting multiple organ systems. Common issues include mucous plugging of the airway, lung inflammation, chronic pulmonary infections, intestinal malabsorption, and malnutrition. Universal screening of newborns for CF is recommended in many countries. CF can be diagnosed based on clinical evidence of disease along with genetic testing or other laboratory evidence of chloride channel dysfunction. Pulmonary system dysfunction causes the most morbidity and mortality. Pulmonary function testing is the primary modality used to monitor CF progression. Therapies include chest physiotherapy, mucolytics, antibiotics, anti-inflammatory drugs, targeted therapies, and vaccines. Dysfunction of the exocrine pancreas and gastrointestinal tract leads to malabsorption, malnutrition, and intestinal obstruction. Nutrition should be optimized with adequate calories, pancreatic enzymes, and appropriate dietary supplements. Complications, including acute pulmonary exacerbations, gastrointestinal conditions, chronic rhinosinusitis, CF-related diabetes, osteoporosis, infertility, and psychosocial issues, must be managed. At the appropriate time, lung transplantation and end-of-life issues must be addressed.

Serotype/serogroup-specific antibiotic non-susceptibility of invasive and non-invasive Streptococcus pneumoniae, Switzerland, 2004 to 2014.

Concurrent analysis of antibiotic resistance of colonising and invasive Streptococcus pneumoniae gives a more accurate picture than looking at either of them separately. Therefore, we analysed 2,129 non-invasive and 10,996 invasive pneumococcal isolates from Switzerland from 2004 to 2014, which spans the time before and after the introduction of the heptavalent (PCV7) and 13-valent (PCV13) conjugated pneumococcal polysaccharide vaccines. Serotype/serogroup information was linked with all antibiotic resistance profiles. During the study period, the proportion of non-susceptible non-invasive and invasive isolates significantly decreased for penicillin, ceftriaxone, erythromycin and trimethoprim/sulfamethoxazole (TMP-SMX). This was most apparent in non-invasive isolates from study subjects younger than five years (penicillin (p = 0.006), erythromycin (p = 0.01) and TMP-SMX (p = 0.002)). Resistant serotypes/serogroups included in PCV7 and/or PCV13 decreased and were replaced by non-PCV13 serotypes (6C and 15B/C). Serotype/serogroup-specific antibiotic resistance rates were comparable between invasive and non-invasive isolates. Adjusted odds ratios of serotype/serogroup-specific penicillin resistance were significantly higher in the west of Switzerland for serotype 6B (1.8; 95% confidence interval (CI): 1.4-4.8), 9V (3.4; 95% CI: 2.0-5.7), 14 (5.3; 95% CI: 3.8-7.5), 19A (2.2; 95% CI: 1.6-3.1) and 19F (3.1; 95% CI: 2.1-4.6), probably due to variations in the antibiotic consumption.

Preventative Care in the Patient with Inflammatory Bowel Disease: What Is New?

Patients with inflammatory bowel disease (IBD) do not receive routine preventative care at the same rate as general medical patients. This patient population is at increased risk of vaccine preventable illness such as influenza and pneumococcal pneumonia. This review will discuss health maintenance needs and preventative care issues in patients with IBD.

Effectiveness of the 10-Valent Pneumococcal Conjugate Vaccine (PCV-10) in Children in Chile: A Nested Case-Control Study Using Nationwide Pneumonia Morbidity and Mortality Surveillance Data.

BACKGROUND: The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Chilean National Immunization Program (NIP) in January 2011 with a 3+1 schedule (2, 4, 6 and 12 months) without catch-up vaccination. We evaluated the effectiveness of PCV10 on pneumonia morbidity and mortality among infants during the first two years after vaccine introduction. METHODS: This is a population-based nested case-control study using four merged nationwide case-based electronic health data registries: live birth, vaccination, hospitalization and mortality. Children born in 2010 and 2011 were followed from two moths of age for a period of two years. Using four different case definitions of pneumonia hospitalization and/or mortality (all-cause and pneumonia related deaths), all cases and four randomly selected matched controls per case were selected. Controls were matched to cases on analysis time. Vaccination status was then assessed. Vaccine effectiveness (VE) was estimated using conditional logistic regression. RESULTS: There were a total of 497,996 children in the 2010 and 2011 Chilean live-birth cohorts. PCV10 VE was 11.2% (95%CI 8.5-13.6) when all pneumonia hospitalizations and deaths were used to define cases. VE increased to 20.7 (95%CI 17.3-23.8) when ICD10 codes used to denote viral pneumonia were excluded from the case definition. VE estimates on pneumonia deaths and all-cause deaths were 71.5 (95%CI 9.0-91.8) and 34.8 (95% CI 23.7-44.4), respectively. CONCLUSION: PCV10 vaccination substantially reduced the number of hospitalizations due to pneumonia and deaths due to pneumonia and to all-causes over this study period. Our findings also reinforce the importance of having quality health information systems for measuring VE.

Multivalent Pneumococcal Protein Vaccines Comprising Pneumolysoid with Epitopes/Fragments of CbpA and/or PspA Elicit Strong and Broad Protection.

Immunization with the pneumococcal proteins pneumolysin (Ply), choline binding protein A (CbpA), or pneumococcal surface protein A (PspA) elicits protective responses against invasive pneumococcal disease in animal models. In this study, we used different mouse models to test the efficacy of a variety of multivalent protein-based vaccines that comprised various combinations of full-length or peptide regions of the immunogens Ply, CbpA, or PspA: Ply toxoid with the L460D substitution (referred to herein as L460D); L460D fused with protective peptide epitopes from CbpA (YPT-L460D-NEEK [YLN]); L460D fused with the CD2 peptide containing the proline-rich region (PRR) of PspA (CD2-L460D); a combination of L460D and H70 (L460D+H70), a slightly larger PspA-derived peptide containing the PRR and the SM1 region; H70+YLN; and other combinations. Each mouse was immunized either intraperitoneally (i.p.) or subcutaneously (s.c.) with three doses (at 2-week intervals) of the various antigen combinations in alum adjuvant and then challenged in mouse models featuring different infection routes with multiple Streptococcus pneumoniae strains. In the i.p. infection sepsis model, H70+YLN consistently provided significant protection against three different challenge strains (serotypes 1, 2, and 6A); the CD2+YLN and H70+L460D combinations also elicited significant protection. Protection against intravenous (i.v.) sepsis (type 3 and 6A challenge strains) was largely dependent on PspA-derived antigen components, and the most protection was elicited by H70 with or without L460D or YLN. In a type 4 intratracheal (i.t.) challenge model that results in progression to meningitis, antigen combinations that contained YLN elicited the strongest protection. Thus, the trivalent antigen combination of H70+YLN elicited the strongest and broadest protection in diverse pneumococcal challenge models.

Linezolid decreases susceptibility to secondary bacterial pneumonia postinfluenza infection in mice through its effects on IFN-γ.

Influenza infection predisposes patients to secondary bacterial pneumonia that contributes significantly to morbidity and mortality. Although this association is well documented, the mechanisms that govern this synergism are poorly understood. A window of hyporesponsiveness following influenza infection has been associated with a substantial increase in local and systemic IFN-γ concentrations. Recent data suggest that the oxazolidinone antibiotic linezolid decreases IFN-γ and TNF-α production in vitro from stimulated PBMCs. We therefore sought to determine whether linezolid would reverse immune hyporesponsiveness after influenza infection in mice through its effects on IFN-γ. In vivo dose-response studies demonstrated that oral linezolid administration sufficiently decreased bronchoalveolar lavage fluid levels of IFN-γ at day 7 postinfluenza infection in a dose-dependent manner. The drug also decreased morbidity as measured by weight loss compared with vehicle-treated controls. When mice were challenged intranasally with Streptococcus pneumoniae 7 d postinfection with influenza, linezolid pretreatment led to decreased IFN-γ and TNF-α production, decreased weight loss, and lower bacterial burdens at 24 h postbacterial infection in comparison with vehicle-treated controls. To determine whether these effects were due to suppression of IFN-γ, linezolid-treated animals were given intranasal instillations of rIFN-γ before challenge with S. pneumoniae. This partially reversed the protective effects observed in the linezolid-treated mice, suggesting that the modulatory effects of linezolid are mediated partially by its ability to blunt IFN-γ production. These results suggest that IFN-γ, and potentially TNF-α, may be useful drug targets for prophylaxis against secondary bacterial pneumonia following influenza infection.

To save children's lives, China should adopt an initiative to speed introduction of pneumonia vaccines.

Despite rapid economic development, China has not yet incorporated into its national childhood immunization program vaccines against Streptococcus pneumoniae and Haemophilus influenzae type b. Both vaccines can prevent pneumonia, the leading infectious disease killer of young children in China. In contrast, the other World Health Organization member nations with the ten largest birth cohorts have included H. influenzae type b in their national childhood immunization programs, and many of the world's wealthiest and poorest countries have done the same with S. pneumoniae. In this article we review what is known about S. pneumoniae and H. influenzae type b in China, and we make recommendations for how to accelerate the use of vaccines against these pathogens in that country. We propose that China adopt a "Chinese Accelerated Vaccine Initiative" modeled after other successful global programs. This broad effort would marshal the evidence and commitment needed to change vaccine policy, then develop and implement a plan for a sustainable, affordable supply of these and other new vaccines.

Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence.

Rapamycin, a potent immunomodulatory drug, has shown promise in the amelioration of numerous age-associated diseases including cancer, Alzheimer's disease and cardiac hypertrophy. Yet the elderly, the population most likely to receive therapeutic rapamycin, are already at increased risk for infectious disease; thus concern exists that rapamycin may exacerbate age-associated immune dysfunctions and worsen infection outcomes. Herein, we examined the impact of enteric delivered rapamycin monotherapy (eRapa) on the susceptibility of aged (22-24month) C57BL/6 mice to Streptococcus pneumoniae, the leading bacterial cause of community-acquired pneumonia. Following challenge with S. pneumoniae, administration of eRapa conferred modest protection against mortality. Reduced mortality was the result of diminished lung damage rather than reduced bacterial burden. eRapa had no effect on basal levels of Interleukin (IL)-1α, IL-6, IL-10, IL-12p70, KC, Interferon-γ, Tumor necrosis factor α and Monocyte chemotactic protein-1 in whole lung homogenates or during pneumococcal pneumonia. Previously we have demonstrated that cellular senescence enhances permissiveness for bacterial pneumonia through increased expression of the bacterial ligands Laminin receptor (LR), Platelet-activating factor receptor (PAFr) and Cytokeratin 10 (K10). These proteins are co-opted by S. pneumoniae and other respiratory tract pathogens for host cell attachment during lung infection. UM-HET3 mice on eRapa had reduced lung cellular senescence as determined by levels of the senescence markers p21 and pRB, but not mH2A.1. Mice on eRapa also had marked reductions in PAFr, LR, and K10. We conclude that eRapa protected aged mice against pneumonia through reduced lung cellular senescence, which in turn, lowered bacterial ligand expression.

Newborn vitamin A supplementation does not affect nasopharyngeal carriage of Streptococcus pneumoniae in Bangladeshi infants at age 3 months.

Nasopharyngeal (NP) carriage of S. pneumoniae (Spn) is a risk factor for pneumococcal disease and its transmission. We assessed the impact of vitamin A (VA) supplementation shortly after birth in reducing Spn colonization in early infancy in rural Bangladesh. We recruited 500 infants participating in a cluster-randomized trial that reported a 15% reduction in mortality following receipt of an oral dose of VA (52.25 µmol) compared to placebo. NP specimens were collected at the age of 3 mo to study the effect of VA on the prevalence of culture-confirmed Spn. Analyses were conducted by intention to treat. Spn carriage prevalence did not differ between VA and placebo recipients [OR = 0.83 (95% CI: 0.55-1.27); P = 0.390]. Spn carriage at the age of 3 mo was not lowered by VA given at birth. Results are similar to those from an Indian study in which impact on Spn carriage was assessed at the age of 4 mo [OR = 0.73 (95% CI: 0.48-1.10); P = 0.128]. The point estimate of the pooled effect size for the 2 studies is OR = 0.78 [(95% CI: 0.58-1.04); P = 0.095], which may imply a modest impact on carriage. If so, then the evidence thus far would suggest that Spn carriage reduction is unlikely to be a primary ancillary benefit of newborn VA supplementation.

The cost-burden of paediatric pneumococcal disease in Sweden and the potential cost-effectiveness of prevention using 7-valent pneumococcal vaccine.

AIMS: A cost-effectiveness model was used to estimate the change in disease burden that might be expected if PCV7 was included as part of the routine 3-dose vaccination schedule in Sweden. METHODS: An economic model was populated with data from the main clinical PCV7 efficacy trials, demographic data from government sources, surveillance and epidemiologic data from the US and Nordic region, and average treatment costs, considering the impact of disease on the whole national population. RESULTS: The model estimated that PCV7 would prevent 18,856 cases of AOM, 684 of pneumonia, 86 of pneumococcal bacteraemia and 21 cases of pneumococcal meningitis in children <10 years, further 221 cases of IPD would be avoided in older children and adults and 397 cases of pneumonia in adults aged 18-39 years. Annually, 4 childhood (<10 years) deaths and 39 deaths in older children and adults would be prevented, resulting in an annual saving of 632 life years. The reduction of cost for the society was estimated to 27.9 (-205, +160) million SEK. The sensitivity analysis showed that it was most sensitive to the efficacy of the vaccine against AOM, the cost of managing infections and the incidence of all disease. CONCLUSION: This model demonstrates that implementing a universal vaccine programme in Sweden with PCV7 would be cost-effective with an estimated net reduction of costs for the society.