Meningococcal ACWYX Conjugate Vaccine in 2-to-29-Year-Olds in Mali and Gambia.

BACKGROUND: An effective, affordable, multivalent meningococcal conjugate vaccine is needed to prevent epidemic meningitis in the African meningitis belt. Data on the safety and immunogenicity of NmCV-5, a pentavalent vaccine targeting the A, C, W, Y, and X serogroups, have been limited. METHODS: We conducted a phase 3, noninferiority trial involving healthy 2-to-29-year-olds in Mali and Gambia. Participants were randomly assigned in a 2:1 ratio to receive a single intramuscular dose of NmCV-5 or the quadrivalent vaccine MenACWY-D. Immunogenicity was assessed at day 28. The noninferiority of NmCV-5 to MenACWY-D was assessed on the basis of the difference in the percentage of participants with a seroresponse (defined as prespecified changes in titer; margin, lower limit of the 96% confidence interval [CI] above -10 percentage points) or geometric mean titer (GMT) ratios (margin, lower limit of the 98.98% CI >0.5). Serogroup X responses in the NmCV-5 group were compared with the lowest response among the MenACWY-D serogroups. Safety was also assessed. RESULTS: A total of 1800 participants received NmCV-5 or MenACWY-D. In the NmCV-5 group, the percentage of participants with a seroresponse ranged from 70.5% (95% CI, 67.8 to 73.2) for serogroup A to 98.5% (95% CI, 97.6 to 99.2) for serogroup W; the percentage with a serogroup X response was 97.2% (95% CI, 96.0 to 98.1). The overall difference between the two vaccines in seroresponse for the four shared serogroups ranged from 1.2 percentage points (96% CI, -0.3 to 3.1) for serogroup W to 20.5 percentage points (96% CI, 15.4 to 25.6) for serogroup A. The overall GMT ratios for the four shared serogroups ranged from 1.7 (98.98% CI, 1.5 to 1.9) for serogroup A to 2.8 (98.98% CI, 2.3 to 3.5) for serogroup C. The serogroup X component of the NmCV-5 vaccine generated seroresponses and GMTs that met the prespecified noninferiority criteria. The incidence of systemic adverse events was similar in the two groups (11.1% in the NmCV-5 group and 9.2% in the MenACWY-D group). CONCLUSIONS: For all four serotypes in common with the MenACWY-D vaccine, the NmCV-5 vaccine elicited immune responses that were noninferior to those elicited by the MenACWY-D vaccine. NmCV-5 also elicited immune responses to serogroup X. No safety concerns were evident. (Funded by the U.K. Foreign, Commonwealth, and Development Office and others; ClinicalTrials.gov number, NCT03964012.).

Potential for Maternally Administered Vaccine for Infant Group B Streptococcus.

BACKGROUND: Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants. METHODS: In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds. RESULTS: Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 µg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 µg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation. CONCLUSIONS: GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).

Strengths and weaknesses of pneumococcal conjugate vaccines.

Multivalent vaccines addressing an increasing number of Streptococcus pneumoniae types (7-, 10-, 13-, 15-, 20-valent) have been licensed over the last 22 years. The use of polysaccharide-protein conjugate vaccines has been pivotal in reducing the incidence of invasive pneumococcal disease despite the emergence of non-vaccine serotypes. Notwithstanding its undoubtable success, some weaknesses have called for continuous improvement of pneumococcal vaccination. For instance, despite their inclusion in pneumococcal conjugate vaccines, there are challenges associated with some serotypes. In particular, Streptococcus pneumoniae type 3 remains a major cause of invasive pneumococcal disease in several countries.Here a deep revision of the strengths and weaknesses of the licensed pneumococcal conjugate vaccines and other vaccine candidates currently in clinical development is reported.

Economic burden of acute otitis media, pneumonia, and invasive pneumococcal disease in children in the United States after the introduction of 13-valent pneumococcal conjugate vaccines during 2014-2018.

BACKGROUND: Streptococcus pneumoniae remains a leading cause of morbidity, mortality, and healthcare resource utilization (HRU) among children. This study quantified HRU and cost of acute otitis media (AOM), pneumonia, and invasive pneumococcal disease (IPD). METHODS: The IBM MarketScan® Commercial Claims and Encounters and Multi-State Medicaid databases from 2014 to 2018 were analyzed. Children with AOM, all-cause pneumonia, or IPD episodes were identified using diagnosis codes in inpatient and outpatient claims. HRU and costs were described for each condition in the commercial and Medicaid-insured populations. National estimates of the number of episodes and total cost ($US 2019 for each condition were extrapolated using data from the US Census Bureau. RESULTS: Approximately 6.2 and 5.6 million AOM episodes were identified in commercial and Medicaid-insured children, respectively, during the study period. Mean cost per AOM episode was $329 (SD $1505) for commercial and $184 (SD $1524) for Medicaid-insured children. A total of 619,876 and 531,095 all-cause pneumonia cases were identified among commercial and Medicaid-insured children, respectively. Mean cost per all-cause pneumonia episode was $2304 (SD $32,309) in the commercial and $1682 (SD $19,282) in the Medicaid-insured population. A total of 858 and 1130 IPD episodes were identified among commercial and Medicaid-insured children, respectively. Mean cost per IPD episode was $53,213 (SD $159,904) for commercial and $23,482 (SD $86,209) for the Medicaid-insured population. Nationally, there were over 15.8 million cases of AOM annually, with total estimated cost of $4.3 billion, over 1.5 million cases of pneumonia annually, with total cost of $3.6 billion, and about 2200 IPD episodes annually, for a cost of $98 million. CONCLUSIONS: The economic burden of AOM, pneumonia, and IPD among US children remains substantial. IPD and its manifestations were associated with higher HRU and costs per episode, compared to AOM and all-cause pneumonia. However, owing to their higher frequencies, AOM and all-cause pneumonia were the main contributors to the economic burden of pneumococcal disease nationally. Additional interventions, such as the development of pneumococcal conjugate vaccinees with sustained protection of existing vaccine type serotypes as well as broader inclusion of additional serotypes, are necessary to further reduce the burden of disease caused by these manifestations.

Structure of a protective epitope reveals the importance of acetylation of Neisseria meningitidis serogroup A capsular polysaccharide.

Meningococcal meningitis remains a substantial cause of mortality and morbidity worldwide. Until recently, countries in the African meningitis belt were susceptible to devastating outbreaks, largely attributed to serogroup A Neisseria meningitidis (MenA). Vaccination with glycoconjugates of MenA capsular polysaccharide led to an almost complete elimination of MenA clinical cases. To understand the molecular basis of vaccine-induced protection, we generated a panel of oligosaccharide fragments of different lengths and tested them with polyclonal and monoclonal antibodies by inhibition enzyme-linked immunosorbent assay, surface plasmon resonance, and competitive human serum bactericidal assay, which is a surrogate for protection. The epitope was shown to optimize between three and six repeating units and to be O-acetylated. The molecular interactions between a protective monoclonal antibody and a MenA capsular polysaccharide fragment were further elucidated at the atomic level by saturation transfer difference NMR spectroscopy and X-ray crystallography. The epitope consists of a trisaccharide anchored to the antibody via the O- and N-acetyl moieties through either H-bonding or CH-π interactions. In silico docking showed that 3-O-acetylation of the upstream residue is essential for antibody binding, while O-acetate could be equally accommodated at three and four positions of the other two residues. These results shed light on the mechanism of action of current MenA vaccines and provide a foundation for the rational design of improved therapies.

Impact of Janus kinase inhibitors on antibody response to 13-valent pneumococcal conjugate vaccine in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the antibody response to 13-valent pneumococcal conjugate vaccine (PCV13) in patients with rheumatoid arthritis receiving Janus kinase inhibitors (JAKIs). METHODS: Fifty-three patients receiving methotrexate (MTX; n = 10), JAKI (n = 20), or MTX + JAKI (n = 23) were vaccinated with PCV13. Serum concentrations of immunoglobulin G (IgG) antibodies to 13 pneumococcal serotype capsular polysaccharides were quantified before and 4-6 weeks after vaccination. Positive antibody response was defined as a 2-fold or more increase in IgG concentrations from prevaccination levels. RESULTS: After vaccination, IgG concentrations significantly increased in all treatment groups (P <0.001), but fold increases (postvaccination to prevaccination ratios) were different among treatment groups (9.30 for MTX, 6.36 for JAKI, and 3.46 for combination therapy). Positive antibody response rates were comparable between the MTX group (90%) and the JAKI group (95%) but lower in the MTX + JAKI group (52.2%). In a multivariable logistic regression analysis, the combination therapy was the only factor associated with a reduced antibody response to PCV13. No severe adverse events were observed in any treatment group. CONCLUSION: Although JAKIs do not impair PCV13 immunogenicity in rheumatoid arthritis patients, the combination of MTX with JAKI can reduce the antibody response in this patient population.

Clinical Characteristics and Treatment Strategies for Group B Streptococcus (GBS) Infection in Pediatrics: A Systematic Review.

Background and Objectives: Group B streptococcus (GBS) is the leading cause of infections in neonates with high fatality rates. GBS is caused by the streptococcus bacterium known as streptococcus agalactiae, which is highly contagious and can be transmitted from pregnant women to infants. GBS infection can occur as an early onset or late-onset infection and has different treatment strategies. Antibiotics are effective in treating GBS infections at early stages. The aim of this systematic review was to summarize the clinical characteristics and treatment strategies for GBS, with a focus on antibiotics. Material and Methods: The findings of this review were reported in accordance with the PRISMA 2020 guidelines and a flow diagram of the study selection process, a summary of the included studies, a description of the study characteristics, a summary of the results, a discussion of the implications of the findings, and a conclusion are included. Overall, the authors followed a rigorous methodology to ensure that this review is comprehensive and inclusive of relevant studies on GBS infection and its treatment. Results: Overall, 940 studies were reviewed and only the most relevant 22 studies were included in the systematic review. This review describes the characteristics of patients in different studies related to early onset GBS disease and presents various treatment strategies and outcomes for GBS infection in pediatrics. The studies suggest that preventive measures, risk-based intrapartum antibiotic prophylaxis, and maternal vaccination can significantly reduce the burden of GBS disease, but late-onset GBS disease remains a concern, and more strategies are required to decrease its rate. Improvement is needed in the management of the risk factors of GBS. A conjugate vaccine with a serotype (Ia, Ib, II, III, and V) has been proven effective in the prevention of GBS in neonates. Moreover, penicillin is an important core antibiotic for treating early onset GBS (EOD). Conclusions: This systematic review summarizes the treatment comparison for GBS infections in neonates, with a primary focus on antibiotics. IAP (intrapartum antibiotic prophylaxis) according to guidelines, antenatal screening, and the development of a conjugate vaccine may be effective and could lower the incidence of the disease.

[Effectiveness of 13-valent pneumococcal conjugate vaccine against invasive disease caused by serotype 19A in children: a meta-analysis].

Objective: Using Meta-analysis to evaluate the vaccine effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) against invasive Streptococcus pneumoniae disease (IPD) caused by serotype 19A in children <5 years old. Methods: "Streptococcus pneumoniae infection""invasive pneumococcal disease""13-valent pneumococcal polysaccharide conjugate vaccine""PCV13""effectiveness""infant""child" and related terms were searched from China National Knowledge Infrastructure (CNKI), WANFANG DATA, PubMed, SCOPUS and Web of science with no limited on language, region and research institution. The retrieval time was limited from January 2010 to February 2023 and cohort study, case-control study and randomized controlled trial were included. Data were extracted from eligible studies by two independent reviewers, and after study quality assessment by NOS scale, Meta-analysis was completed using Stata 16.0 software. Results: A total of 2 340 related literatures were searched, and 10 literatures were finally included, including 5 case-control studies and 5 indirect cohort studies, which showed good literature quality. The vaccine effectiveness against serotype 19A IPD of PCV13 in children was 83.91% (95%CI: 78.92%-88.89%), and the subgroup analysis (P=0.240) showed there was no significant difference among the case-control study (VE=87.34%, 95%CI:79.74%-94.94%) and the indirect cohort study (VE=81.30%, 95%CI:74.69%-87.92%). The funnel plot and Egger test suggested that the possibility of publication bias was small. Conclusion: The present evidence indicates that PCV13 has a good vaccine effectiveness against serotype 19A IPD in children, and it is recommended to further increase the vaccination rate of PCV13 to reduce the disease burden of IPD in children <5 years old.

Use of 15-Valent Pneumococcal Conjugate Vaccine and 20-Valent Pneumococcal Conjugate Vaccine Among U.S. Adults: Updated Recommendations of the Advisory Committee on Immunization Practices - United States, 2022.

In 2021, 20-valent pneumococcal conjugate vaccine (PCV) (PCV20) (Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.) and 15-valent PCV (PCV15) (Merck Sharp & Dohme Corp.) were licensed by the Food and Drug Administration for adults aged ≥18 years, based on studies that compared antibody responses to PCV20 and PCV15 with those to 13-valent PCV (PCV13) (Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.). Antibody responses to two additional serotypes included in PCV15 were compared to corresponding responses after PCV13 vaccination, and antibody responses to seven additional serotypes included in PCV20 were compared with those to the 23-valent pneumococcal polysaccharide vaccine (PPSV23) (Merck Sharp & Dohme Corp.). On October 20, 2021, the Advisory Committee on Immunization Practices (ACIP) recommended use of either PCV20 alone or PCV15 in series with PPSV23 for all adults aged ≥65 years, and for adults aged 19-64 years with certain underlying medical conditions or other risk factors* who have not previously received a PCV or whose previous vaccination history is unknown. ACIP employed the Evidence to Recommendation (EtR) framework,† using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE)§ approach to guide its deliberations regarding use of these vaccines. Before this, PCV13 and PPSV23 were recommended for use for U.S. adults and the recommendations varied by age and risk groups. This was simplified in the new recommendations.

Healthcare Costs for Pneumococcal Disease in the Era of Infant Immunization With 13-Valent Pneumococcal Conjugate Vaccine: A Population-Based Study.

OBJECTIVES: Invasive pneumococcal disease (IPD) and a variety of clinical syndromes caused by pneumococci, such as acute otitis media (AOM), acute sinusitis (AS), and community-acquired pneumonia (CAP), cause a substantial burden on healthcare systems. Few studies have explored the short-term financial burden of pneumococcal disease after the 13-valent pneumococcal conjugate vaccine (PCV13) introduction in the infant immunization programs. This population-based study evaluated changes in costs associated with healthcare utilization for pneumococcal disease after the PCV13 introduction in the infant immunization program in British Columbia, Canada. METHODS: Individuals with pneumococcal disease were identified using provincial administrative data for the 2000 to 2018 period. Total direct healthcare costs were determined using case-mix methodology for hospitalization and fee-for-service codes for outpatient visits and medications dispensed. Costs were adjusted to 2018 Canadian dollars. Changes in the annual healthcare costs were evaluated across vaccine eras (pre-PCV13, 2000-2010; PCV13, 2011-2018) using generalized linear models, adjusting for the 7-valent pneumococcal conjugate vaccine program (2004-2010). RESULTS: During the 19-year study period, pneumococcal disease resulted in 6.3 million cases among 85 million total patient-years, resulting in total healthcare costs of $7.9 billion. More than 6.2 million cases were treated in outpatient setting, costing $0.65 billion (8% of total costs associated with pneumococcal disease treatment), whereas 370 000 hospitalized cases were 3% of all cases, which accrued $7.25 billion (92% of total costs) in costs. Healthcare costs for all studied infections nearly doubled over the study period from $248 million in 2000 to $476 million in 2018 (P = .003). In contrast, there were large declines in total annual costs in the PCV13 era for IPD (adjusted relative rate (aRR) 0.73; 95% confidence interval [CI] 0.56-0.95; P = .032), AOM (aRR 0.70; 95% CI 0.59-0.83; P = .001), and AS (aRR 0.68; 95% CI 0.54-0.85; P = .004) compared with the pre-PCV13 era. Total costs increased marginally in the PCV13 era for all-cause CAP (aRR 1.04; 95% CI 0.94-1.15; P = .484). CONCLUSIONS: This study confirms a temporal association in declining economic burden for IPD, AOM, and AS after the PCV13 introduction. Nevertheless, the total economic burden continues to be high in the PCV13 era, mainly driven by increasing CAP costs.

Prevention of pneumococcal infections in childhood: two decades of progress.

PURPOSE OF REVIEW: This review highlights progress in combating pediatric pneumococcal disease in the era of pneumococcal conjugate vaccines (PCVs). This review is timely given the development of increased valency PCVs for potential use in children. RECENT FINDINGS: Countries implementing vaccination programs with PCVs have witnessed dramatic reductions in cases of childhood invasive pneumococcal disease (IPD). In the US, the largest decline of IPD followed the introduction of 7-valent PCV with additional decreases following the switch to 13-valent PCV (PCV13). Despite these gains, IPD still occurs in the US but at much lower rates. Likewise, pneumonia hospitalizations and office visits for otitis media have decreased. Nasopharyngeal colonization with pneumococci has persisted due to replacement by nonvaccine serotypes: colonizing non-PCV13 serotypes have less invasive potential. The PCV era has also been marked by reductions in the proportions of pneumococcus showing nonsusceptibility or resistance to some antimicrobial agents. Furthermore, PCVs have an excellent safety profile. SUMMARY: Despite proven safety and efficacy, childhood vaccination programs in some countries do not include PCVs, resulting in the majority of global deaths attributable to pneumococcus. Increased worldwide vaccination of children and the development of higher valency vaccines holds additional promise for further reductions in childhood IPD.

Rapid progressive destruction of the cochleae in an infant due to pneumococcal meningitis.

The widespread adoption of pneumococcal conjugate vaccines has reduced the incidence of Streptococcus pneumoniae infections, but has also led to the emergence of infections due to non-vaccine serotypes. A 15-month-old girl was referred to our hospital with suspected meningitis. S. pneumoniae was isolated from her cerebrospinal fluid. She was initially treated with a combination of cefotaxime and vancomycin, followed by ampicillin and vancomycin. After 7 days, the patient's condition improved and she was transferred to the general ward; however, her mother noted signs of hearing difficulties. On the 16th day of admission, we performed an auditory brainstem response test, which suggested severe bilateral hearing impairment. This was confirmed using an auditory steady-state response test after consulting with otolaryngologists. Magnetic resonance imaging revealed fibrosis of both cochleae with labyrinthitis. The patient underwent emergency cochlear implantation at a different hospital. The S. pneumoniae isolate was later identified to be serotype 10A with a PBP2x mutation, which is not covered by the conjugate vaccine and has reduced cephalosporin susceptibility. This case was characterized by highly rapid cochlear destruction, and an earlier otolaryngologist consultation may have provided a more well-organized surgery plan. Pediatricians are urged to promptly consult with otolaryngologists for patients with similar indications.

[Apexxnar®, 20-valent pneumococcal conjugate vaccine]. / Apexxnar®, vaccin anti-pneumococcique conjugué avec 20 sérotypes.

Streptococcus pneumoniae infections cause bacteremic and non-bacteremic community-acquired pneumonia and invasive pneumococcal diseases (IPD) such as bacteremia, sepsis and acute meningitis. They are potentially lethal. Although polysaccharide vaccines (PPV23, Pneumovax 23®) have already provided protection in at-risk individuals, they have been imperfect, mainly because the development of anti-polysaccharide antibodies occurs without the help of T cells. The introduction of immunogenic protein conjugate vaccines (ICVs) has overcome this problem and provided better and longer lasting protection. The first available vaccine of this type for adults was Prevenar 13®, targeting 13 polysaccharides of S. pneumoniae (PCV13). A new vaccine, Apexxnar®, targeting 20 polysaccharides (PCV20), the 13 of Prevenar 13®, to which 7 other serotypes considered to be equally responsible for invasive infections have been added, has recently been launched. Clinical studies have demonstrated a good immunogenic response against all 20 serotypes in adult patients who are either vaccine-naive or previously vaccinated with PPV23 and/or PCV13. Furthermore, the tolerance of the PCV20 vaccine was found to be comparable to that of Prevenar 13®. Vaccination with PCV20 involves a single injection. The Belgian Superior Health Council has recently reiterated the importance of vaccinating at-risk individuals against S. pneumoniae (a vaccination that is still under-performed). It now recommends vaccination with PCV20 (Apexxnar®) as the preferred primary vaccination regimen in high-risk adults with co-morbidities or in good health aged between 65 and 85 years.

Les infections par le Streptococcus pneumoniae sont responsables de pneumonies communautaires bactériémiantes ou non ainsi que de maladies invasives à pneumocoques (MIP) telles que bactériémies, sepsis et méningites aiguës. Elles sont potentiellement létales. Certes, les vaccins polysaccharidiques (PPV23, Pneumovax 23®) ont déjà permis d'assurer une protection chez les personnes à risque, mais de façon imparfaite essentiellement parce que le développement des anticorps anti-polysaccharides se fait sans l'aide des lymphocytes T. La commercialisation des vaccins conjugués (PCV) à une protéine immunogène a permis de remédier à ce problème et d'assurer une meilleure protection plus durable. Le premier vaccin disponible pour les adultes était le Prevenar 13®, ciblant 13 polysaccharides du S. pneumoniae (PCV13). Un nouveau vaccin vient d'être commercialisé, l'Apexxnar®, ciblant 20 polysaccharides (PCV20), les 13 du Prevenar 13® auquels 7 autres sérotypes considérés comme également responsables d'infections invasives ont été ajoutés. Des études cliniques ont démontré une bonne réponse immunogène contre l'ensemble des 20 sérotypes, chez des personnes adultes naïves de vaccination ou déjà vaccinées antérieurement par le PPV23 et/ou le PCV13. Par ailleurs, la tolérance du vaccin PCV20 s'est révélée comparable à celle du Prevenar 13®. La vaccination avec le PCV20 comporte une injection unique. Le Conseil Supérieur de la Santé Belge vient de rappeler l'importance de vacciner les personnes à risque contre S. pneumoniae (vaccination encore trop peu réalisée). Il recommande désormais la vaccination avec le PCV20 (Apexxnar®) comme schéma préférentiel de primo-vaccination chez les personnes adultes à haut risque, avec comorbidités ou en bonne santé âgées entre 65 et 85 ans.

The comparison of exacerbation and pneumonia before and after conjugated pneumococcal vaccination in patients with chronic obstructive pulmonary disease, and the effect of inhaled corticosteroid use on results.

Introduction: Pneumococcal infections and exacerbations are important causes of mortality and morbidity in chronic obstructive pulmonary disease (COPD). The use of inhaled corticosteroids and pneumococcal vaccination are suggested for the control of the disease progression and exacerbations. The aim of this study is to assess the effect of pneumococcal conjugate vaccine on pneumonia and exacerbation in COPD patients using inhaled corticosteroids (ICSs). The secondary aim is to analyze the effect of ICS use and different ICS types, if administered, on exacerbation and pneumonia incidence in the study population. Materials and Methods: Medical records of 108 adult patients with COPD who were vaccinated with the pneumococcal conjugate vaccine (PCV13) were retrospectively evaluated. The number of acute exacerbations and pneumonia within one year before and after vaccination were evaluated in all included COPD patients. The comparison analysis was also performed based on the ICS types. Result: There were statistically significant differences between the mean numbers of pneumonia and exacerbations before and after vaccination (p<0.05). There were no significant differences in the mean pneumonia attacks and acute exacerbations between patients using ICS and not using ICS (p> 0.05). Conclusions: This study revealed that PCV13 provides a significant decrease in both exacerbation and pneumonia episodes in COPD patients. On the other hand, the use of ICSs and the types of ICSs were not found to have adverse effects on pneumonia and acute exacerbations in vaccinated COPD patients.

Global Rotavirus and Pneumococcal Conjugate Vaccine Introductions and the Association With Country Disease Surveillance, 2006-2018.

BACKGROUND: To inform the introduction of pneumococcal conjugate vaccine (PCV) and rotavirus vaccine, the World Health Organization (WHO) established the Global Invasive Bacterial Vaccine-Preventable Disease Surveillance Network (GISN) and the Global Rotavirus Surveillance Network (GRSN) in 2008. We investigated whether participation in these networks or other surveillance was associated with vaccine introduction. METHODS: Between 2006 and 2018, among all WHO member states, we used multivariable models adjusting for economic status to assess (1) the association between surveillance for pneumococcal disease or rotavirus disease, including participation in GISN or GRSN and the introduction of the PCV or the rotavirus vaccine, respectively, and (2) the association between the rotavirus disease burden and the rotavirus vaccine introduction among 56 countries participating in GRSN from 2008 to 2018. RESULTS: Countries that participated in or conducted surveillance for invasive pneumococcal disease or rotavirus disease were 3.5 (95% confidence interval [CI], 1.7-7.1) and 4.2 (95% CI, 2.1-8.6) times more likely to introduce PCV or rotavirus respectively, compared to those without surveillance. Among countries participating in GRSN, there was insufficient evidence to demonstrate an association between countries with higher rotavirus positivity and vaccine introduction. CONCLUSIONS: Surveillance should be incorporated into advocacy strategies to encourage the introduction of vaccines, with countries benefiting from data from, support for, and coordination of international disease surveillance networks.

Immunization with outer membrane vesicles displaying conserved surface polysaccharide antigen elicits broadly antimicrobial antibodies.

Many microbial pathogens produce a ß-(1→6)-linked poly-N-acetyl-d-glucosamine (PNAG) surface capsule, including bacterial, fungal, and protozoan cells. Broadly protective immune responses to this single conserved polysaccharide antigen in animals are possible but only when a deacetylated poly-N-acetyl-d-glucosamine (dPNAG; <30% acetate) glycoform is administered as a conjugate to a carrier protein. Unfortunately, conventional methods for natural extraction or chemical synthesis of dPNAG and its subsequent conjugation to protein carriers can be technically demanding and expensive. Here, we describe an alternative strategy for creating broadly protective vaccine candidates that involved coordinating recombinant poly-N-acetyl-d-glucosamine (rPNAG) biosynthesis with outer membrane vesicle (OMV) formation in laboratory strains of Escherichia coli The glycosylated outer membrane vesicles (glycOMVs) released by these engineered bacteria were decorated with the PNAG glycopolymer and induced high titers of PNAG-specific IgG antibodies after immunization in mice. When a Staphylococcus aureus enzyme responsible for PNAG deacetylation was additionally expressed in these cells, glycOMVs were generated that elicited antibodies to both highly acetylated PNAG (∼95-100% acetate) and a chemically deacetylated dPNAG derivative (∼15% acetate). These antibodies mediated efficient in vitro killing of two distinct PNAG-positive bacterial species, namely S. aureus and Francisella tularensis subsp. holarctica, and mice immunized with PNAG-containing glycOMVs developed protective immunity against these unrelated pathogens. Collectively, our results reveal the potential of glycOMVs for targeting this conserved polysaccharide antigen and engendering protective immunity against the broad range of pathogens that produce surface PNAG.

Estimating the contribution of different age strata to vaccine serotype pneumococcal transmission in the pre vaccine era: a modelling study.

BACKGROUND: Herd protection through interruption of transmission has contributed greatly to the impact of pneumococcal conjugate vaccines (PCVs) and may enable the use of cost-saving reduced dose schedules. To aid PCV age targeting to achieve herd protection, we estimated which population age groups contribute most to vaccine serotype (VT) pneumococcal transmission. METHODS: We used transmission dynamic models to mirror pre-PCV epidemiology in England and Wales, Finland, Kilifi in Kenya and Nha Trang in Vietnam where data on carriage prevalence in infants, pre-school and school-aged children and adults as well as social contact patterns was available. We used Markov Chain Monte Carlo methods to fit the models and then extracted the per capita and population-based contribution of different age groups to VT transmission. RESULTS: We estimated that in all settings, < 1-year-old infants cause very frequent secondary vaccine type pneumococcal infections per capita. However, 1-5-year-old children have the much higher contribution to the force of infection at 51% (28, 73), 40% (27, 59), 37% (28, 48) and 67% (41, 86) of the total infection pressure in E&W, Finland, Kilifi and Nha Trang, respectively. Unlike the other settings, school-aged children in Kilifi were the dominant source for VT infections with 42% (29, 54) of all infections caused. Similarly, we estimated that the main source of VT infections in infants are pre-school children and that in Kilifi 39% (28, 51) of VT infant infections stem from school-aged children whereas this was below 15% in the other settings. CONCLUSION: Vaccine protection of pre-school children is key for PCV herd immunity. However, in high transmission settings, school-aged children may substantially contribute to transmission and likely have waned much of their PCV protection under currently recommended schedules.

Estimating Serotype-specific Efficacy of Pneumococcal Conjugate Vaccines Using Hierarchical Models.

Pneumococcal conjugate vaccines target 10 or 13 specific serotypes. To evaluate the overall efficacy of these products, the vaccine-targeted serotypes are typically aggregated into a single group. However, it is often desirable to evaluate variations in effects for different serotypes. These serotype-specific estimates are often based on small counts, resulting in a high degree of uncertainty (i.e., large standard errors and wide confidence intervals). An alternative is to use a hierarchical Bayesian statistical model, which estimates overall effectiveness while simultaneously providing estimates of serotype-specific vaccine effects. These shrunken serotype-specific estimators often have smaller mean squared errors (MSEs) than unbiased versions due to a large decrease in posterior uncertainty. We reanalyzed published data from a randomized controlled trial on the efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) against community-acquired pneumonia caused by vaccine-targeted serotype using a hierarchical model. This model provides a potential framework for obtaining estimates of serotype-specific vaccine effects with reduced MSEs.

Expanding the Scope of Ugi Multicomponent Bioconjugation to Produce Pneumococcal Multivalent Glycoconjugates as Vaccine Candidates.

Conjugate vaccines against encapsulated pathogens like Streptococcus pneumoniae face many challenges, including the existence of multiple serotypes with a diverse global distribution that constantly requires new formulations and higher coverage. Multivalency is usually achieved by combining capsular polysaccharide-protein conjugates from invasive serotypes, and for S. pneumoniae, this has evolved from 7- up to 20-valent vaccines. These glycoconjugate formulations often contain high concentrations of carrier proteins, which may negatively affect glycoconjugate immune response. This work broadens the scope of an efficient multicomponent strategy, leading to multivalent pneumococcal glycoconjugates assembled in a single synthetic operation. The bioconjugation method, based on the Ugi four-component reaction, enables the one-pot incorporation of two different polysaccharide antigens to a tetanus toxoid carrier, thus representing the fastest approach to achieve multivalency. The reported glycoconjugates incorporate three combinations of capsular polysaccharides 1, 6B, 14, and 18C from S. pneumoniae. The glycoconjugates were able to elicit functional specific antibodies against pneumococcal strains comparable to those shown by mixtures of the two monovalent glycoconjugates.

The potential role of pneumococcal conjugate vaccine in reducing acute respiratory inflammation in community-acquired pneumococcal pneumonia.

BACKGROUND: Pneumococcal conjugate vaccine (PCV) reduces both invasive pneumococcal disease (IPD) and other pneumococcal infections worldwide. We investigated the impact of stepwise implementation of childhood PCV programs on the prevalence of pneumococcal pneumonia, severity of acute inflammation, and associations between breakthrough pneumonia and pneumococcal serotypes in Taiwan. METHODS: In total, 983 children diagnosed with community-acquired pneumococcal pneumonia were enrolled between January 2010 and December 2015. RESULTS: Proportions of pneumococcal vaccinations increased each year in age-stratified groups with PCV7 (32.2%) as the majority, followed by PCV13 (12.2%). The proportion of pneumococcal pneumonia decreased each year in age-stratified groups, especially in 2-5 year group. Serotype 19A is the leading serotype either in vaccinated (6.4%) or unvaccinated patients (5.2%). In particular, vaccinated patients had significantly higher lowest WBC, lower neutrophils, lower lymphocytes and lower CRP values than non-vaccinated patients (p < 0.05). After stratifying patients by breakthrough infection, those with breakthrough pneumococcal infection with vaccine coverage serotypes had more severe pneumonia disease (p < 0.05). CONCLUSION: Systematic childhood pneumococcal vaccination reduced the prevalence of community-acquired pneumococcal pneumonia, especially in 2-5 year group. Serotype 19A was the major serotype for all vaccine types in patients with pneumococcal pneumonia and severity of acute inflammatory response was reduced in vaccinated patients.