Long-term predominance in childhood colonization of the multidrug-resistant lineage 6C/ST386 of Streptococcus pneumoniae after universal immunization with the 10-valent pneumococcal conjugate vaccine in Brazil.

BACKGROUND: A study conducted in the city of Niterói/RJ, four years after the introduction of the pneumococcal conjugate vaccine in Brazil, reported the emergence of non-vaccine serotype 6C Streptococcus pneumoniae associated with carriage in children. The multidrug-resistant (MDR) lineage ST386 was predominant among 6C isolates. A subsequent study, in 2019, reported the continued prevalence of 6C as the main serotype. This study aims to determine the genetic lineages of serotype 6C S. pneumoniae obtained from the 2019 study and evaluate the status of ST386 in this population. METHODS: Serotype 6C S. pneumoniae isolates were obtained during the 2019 study. Lineages were determined by MLST and changes in ST386 status between 2014 and 2019 were verified by a two-tailed Fisher's exact test. RESULTS: Of the 16 serotype 6C isolates recovered during 2019, 10 (62.5 %) belonged to ST386, remaining predominant in the population. The second most frequent was ST2777 represented by four (25 %) isolates. Both ST63 and ST3280 only had one (6.25 %) isolate each. Comparison of ST386 proportion between 2014 and 2019 showed no significant changes within the population. CONCLUSIONS: This study was able to confirm the stability on the occurrence of the MDR lineage ST386 in children in our setting nine years after the introduction of PCV10 in Brazil.

Descriptive analysis of safety and immunogenicity profiles of a 15-valent pneumococcal conjugate vaccine between subcutaneous and intramuscular administration in a phase 1 study of healthy Japanese infants (V114-028).

INTRODUCTION: Subcutaneous (SC) administration is typically used for pediatric inactivated vaccines in Japan, whereas intramuscular (IM) administration is used outside Japan. We previously reported the safety and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine (PCV), administered subcutaneously and intramuscularly in a Japanese phase 1 study (V114-028). Here, we report secondary descriptive analyses on V114 groups of the study to further assess the safety and immunogenicity profiles of V114 between the administration routes. METHODS: A total of 133 healthy Japanese infants were randomized to receive V114-SC (n = 44), V114-IM (n = 45), or PCV13-SC (n = 44) at approximately 3, 4, 5, and 12-15 months of age. Adverse events (AEs) from Days 1-14 post-vaccination and vaccine-related serious AEs from Day 1 to 1-month post-dose 4 were reported. Serotype-specific immunoglobulin G (IgG) responses were measured across the vaccination series. RESULTS: Proportions of participants with solicited systemic AEs (irritability, somnolence, decreased appetite, and urticaria) and pyrexia were generally comparable between the groups. Compared with V114-SC, patients receiving V114-IM had a lower incidence of irritability and somnolence, and higher incidence of decreased appetite. Proportion of participants with solicited injection-site erythema was lower with V114-IM (82.2%) than V114-SC (100.0%). Those with other solicited injection-site AEs (induration, swelling, and pain) were generally comparable between the groups, with lower observed proportions with V114-IM. Serotype-specific IgG responses were also generally comparable between the groups including at pre-toddler dose. CONCLUSIONS: These results suggest the utility of IM administration as an option for V114 vaccination in Japanese infants.

Serotype distribution and antimicrobial susceptibility of Streptococcus pneumoniae isolates cultured from Japanese adult patients with community-acquired pneumonia in Goto City, Japan.

Streptococcus pneumoniae is an important cause of community-acquired pneumonia (CAP) in Japan. Here, we report the serotype distribution and antimicrobial susceptibility of cultured pneumococcal isolates from Japanese adults aged ≥18 years with CAP. This was a prospective, population-based, active surveillance study conducted in Goto City, Japan from December 2015 to November 2020. Pneumococcal isolates from sterile sites (blood and pleural fluid) and non-sterile sites (sputum and bronchoalveolar lavage) were cultured as part of the standard of care. S. pneumoniae were serotyped using the Quellung reaction. Antimicrobial susceptibility was tested using microdilution and interpreted according to the Clinical and Laboratory Standards Institute criteria. Isolates resistant to erythromycin were phenotyped using the triple-risk test and genotyped by polymerase chain reaction. A total of 156 pneumococcal isolates were collected (138 from sputum, 15 from blood, and 3 from bronchoalveolar lavage) from 1992 patients. Of these, 142 were non-duplicate isolates from unique patients and were included in the analyses. Serotypes contained within the 13-valent pneumococcal conjugate vaccine (PCV13) (including 6C), PCV15 (including 6C), and PCV20 (including 6C and 15C) were detected in 39 (27%), 45 (32%), and 80 (56%) of 142 isolates, respectively. The most common serotypes were 35B (12%), 11A (11%), and 3 (11%). Multidrug resistance (MDR) was detected in 96/142 (68%) isolates. Of the 96 MDR isolates, 31, 32, and 59% were PCV13, PCV15, and PCV20 serotypes, respectively; the most common MDR serotypes were 35B (16%), 6C, 10A, and 15A (9% each), and 3 and 11A (8% each). A total of 119 isolates were resistant to macrolides; 41 (35%) had an M phenotype, 53 (45%) had an iMcLS phenotype, and 25 (21%) had a cMLS phenotype. In conclusion, pneumococcal serotypes 35B, 11A and 3 were most frequently associated with pneumonia and antimicrobial resistance was common among pneumococcal isolates from adults with CAP in Goto City, Japan. Implementing higher-valency PCVs May help reduce vaccine-type CAP among Japanese adults.

Streptococcus pneumoniae Spinal Epidural Abscess in an Immunocompetent Patient.

Epidural abscesses are a rare diagnosis in immunocompetent patients. The most common risk factors linked with spinal epidural abscesses are intravenous drug use, diabetes mellitus, hepatitis, and iatrogenic factors like prior surgery and catheter usage. The thoracic and lumbar spine are the most common sites of these abscesses. Clinical presentation can include back pain, fever, and neurologic deterioration, with back pain occurring in almost two-thirds of patients. Staphylococcus aureus is the most common causative pathogen. We present a 50 male with no significant past medical or family history who presented with progressive back pain for greater than one week, chills and malaise. Cervical and lumbar spinal CT scans identified epidural abscesses at C6/7 and L5/S1. Blood cultures and surgical cultures from washout of the epidural space grew Streptococcus pneumoniae. The patient was treated successfully with a prolonged course of cefazolin for six weeks. S. pneumoniae is a rare cause of epidural abscesses, especially in patients with no known risk factors for invasive disease. This case demonstrates that invasive pneumococcal disease should remain on the differential diagnosis even in immunocompetent patients.

Case Report: Hypocomplementemic urticarial vasculitis syndrome in a pediatric patient with complement factor 1 deficiency.

Urticarial vasculitis (UV) is a type III hypersensitivity reaction, characterized by immune complex deposition in small vessels leading to complement activation. Hypocomplementemic urticarial vasculitis syndrome (HUVS) represents the most severe form of UV, manifesting as chronic and recurrent urticarial skin lesions with leukocytoclastic vasculitis on histology, hypocomplementemia, anti-C1q antibodies, and systemic organ involvement. This case study focuses on an adolescent who initially presented with invasive pneumococcal infection and was later diagnosed with two rare disorders: HUVS and coexisting complement factor 1 (CF1) deficiency by genotyping. The role of CF1 deficiency in the development of HUVS in this patient is uncertain but has not previously been described.

Effect of O-acetylation on the antigenicity and glycoconjugate immunogenicity of the Streptococcus pneumoniae serotype 7F capsular polysaccharide.

Streptococcus pneumoniae is a bacterial pathogen causing diseases as severe as pneumonia, sepsis and meningitis. Commercial pneumococcal conjugate vaccines contain the 7F serotype, which is epidemiologically relevant and highly invasive. This serotype contains an O-acetyl group at the internal L-rhamnose of its polysaccharide repeating unit. Herein we report on the role of the O-acetyl moiety of 7F polysaccharide in both antigen recognition and the induction of a protective antibody response against 7F. Fully and partially de-O-acetylated 7F polysaccharides were chemically prepared and compared with the O-acetylated counterpart in their antigenicity and immunogenicity of their tetanus toxoid glycoconjugates. These comparative studies showed a slight but consistent decrease in the antigenicity for the fully de-O-acetylated polysaccharide, but not for the partly de-O-acetylated variant. The glycoconjugates derived from the O-acetylated and the fully de-O-acetylated polysaccharides had similar sizes and polysaccharide-to-protein ratio, and all proved both to be immunogenic and induce opsonophagocytic responses in mice. Nevertheless, the immune response elicited by the O-acetylated glycoconjugate was better in both quantity and quality, proving that the O-acetyl group is not strictly necessary but also not irrelevant for the antigenicity and immunogenicity of the 7F serotype polysaccharide and its glycoconjugates.

Radiographically confirmed pneumonia in Malawian children and associated pneumococcal carriage after introduction of the 13-valent pneumococcal conjugate vaccine.

BACKGROUND: The 13-valent pneumococcal conjugate vaccine (PCV-13) was introduced in Malawi in 2011 with an expected impact of reducing pneumococcal pneumonia in children. We aimed to describe clinical characteristics and nasopharyngeal (NP) carriage of pneumococcus by serotype in children hospitalized with primary end-point pneumonia (PEP) between 2013 and 19 after the introduction of PCV-13. METHODS: We conducted a secondary analysis of children aged under-5-years hospitalized with acute respiratory illness (ARI) in Malawi. Chest radiographs conducted at admission were read by two independent clinicians according to WHO criteria for PEP, and a third reviewer resolved discordant diagnoses. NP swab specimens were processed and Streptococcus pneumoniae growth was serotyped. Multivariable regression analysis was conducted to assess the association between clinical characteristics, NP serotypes, and PEP. RESULTS: We had complete radiographic and NP serotype data for 500 children, of which 54 isolates were vaccine-type (VT) (10.8%), 165 were non-VT (NVT; 33.0%), and 281 had no pneumococcal growth (56.2%). Among these, 176 (35.2%) had PEP on chest x-ray. Among those with PEP, pneumococcal carriage was documented in 43.8% of cases, and VT serotypes accounted for 10.8%. For children with PEP, we found no association between clinical characteristics and carrying either VT, NVT, or no pneumococcus. CONCLUSION: Carriage of S. pneumoniae remains high among children hospitalized with ARI in Malawi, but children with VT carriage were no more likely to have PEP than children carrying no pneumococcus or those with NVT carriage. There were no differences in clinical characteristics between those carrying VT, NVT, or no pneumococcus.

Pneumococcal surface protein A (PspA) prevents killing of Streptococcus pneumoniae by indolicidin.

Pneumococcal surface protein A (PspA) is an important virulence factor in Streptococcus pneumoniae that binds to lactoferrin and protects the bacterium from the bactericidal action of lactoferricins-cationic peptides released upon lactoferrin proteolysis. The present study investigated if PspA can prevent killing by another cationic peptide, indolicidin. PspA-negative pneumococci were more sensitive to indolicidin-induced killing than bacteria expressing PspA, suggesting that PspA prevents the bactericidal action of indolicidin. Similarly, chemical removal of choline-binding proteins increased sensitivity to indolicidin. The absence of capsule and PspA had an additive effect on pneumococcal killing by the AMP. Furthermore, anti-PspA antibodies enhanced the bactericidal effect of indolicidin on pneumococci, while addition of soluble PspA fragments competitively inhibited indolicidin action. Previous in silico analysis suggests a possible interaction between PspA and indolicidin. Thus, we hypothesize that PspA acts by sequestering indolicidin and preventing it from reaching the bacterial membrane. A specific interaction between PspA and indolicidin was demonstrated by mass spectrometry, confirming that PspA can actively bind to the AMP. These results reinforce the vaccine potential of PspA and suggest a possible mechanism of innate immune evasion employed by pneumococci, which involves binding to cationic peptides and hindering their ability to damage the bacterial membranes.

Effectiveness of the ten- and thirteen-valent pneumococcal conjugate vaccines to prevent serotype 19A invasive pneumococcal disease in Quebec, Canada. A Canadian immunization research network (CIRN) study.

In the province of Quebec, Canada, a 2 + 1 dose pneumococcal conjugate vaccine (PCV) program for children was implemented in 2004. PCV7, PCV10, PCV13 and a mixed PCV10/PCV13 schedule were sequentially used without catch-up. The effectiveness of vaccination schedules to prevent serotype 19A invasive pneumococcal disease (IPD) in <5-year-old children was estimated by the indirect cohort method during 2009-2023. A total of 248 19A IPD cases and 457 IPD controls were included in the analysis. Adjusted vaccine effectiveness (VEa) for ≥1 dose was 57 % [95 %CI: -1 %,82 %] for PCV10 and 62 % [16 %,83 %] for PCV13. VEa for 3 doses was 69 % [17 %,88 %] for PCV10, 76 % [39 %,90 %] for PCV13 and 86 % [64 %,95 %] for the 2PCV10 + 1PCV13 schedule. Protection provided by the PCV10-only schedule tended to be of lower magnitude compared to the two other schedules. The mixed PCV10 + PCV13 schedule showed a protection against 19A IPD at least comparable to that of 3 PCV-13 doses.

Implications of Cross-Reactivity and Cross-Protection for Pneumococcal Vaccine Development.

Pneumococcal vaccines are a cornerstone for the prevention of pneumococcal diseases, reducing morbidity and mortality in children and adults worldwide. Pneumococcal vaccine composition is based on the polysaccharide capsule of Streptococcus pneumoniae, which is one of the most important identified contributors to the pathogen's virulence. Similarities in the structural composition of polysaccharides included in licensed pneumococcal vaccines may result in cross-reactivity of immune response against closely related serotypes, including serotypes not included in the vaccine. Therefore, it is important to understand whether cross-reactive antibodies offer clinical protection against pneumococcal disease. This review explores available evidence of cross-reactivity and cross-protection associated with pneumococcal vaccines, the challenges associated with the assessment of cross-reactivity and cross-protection, and implications for vaccine design and development.

The Divergent Effect of Different Infant Vaccination Schedules of the 13-Valent Pneumococcal Conjugate Vaccine on Serotype-Specific Immunological Memory.

Pneumococcal vaccination schedules are traditionally assessed based on the antibody response. The Memory B Cell (MBC) response has been less studied, despite its role in the magnitude and longevity of protection. We compared the immune response to different vaccination schedules with the 13-valent Pneumococcal Conjugate Vaccine (PCV13) and investigated the relationship between MBCs and the antibody response. Total and pneumococcal serotype (PS)-specific MBCs, their subsets and PS-specific IgG antibodies induced by a 3 + 0 (group A), 2 + 1 (group B) or 3 + 1 (group C) schedule in healthy infants were studied before and 1 month after the last PCV13. The relatively immature IgM+IgD+ MBC subset was the predominant subset in all groups but was larger in group A compared to group B and group C, indicating that age might be a significant parameter of the composition of the MBC pool. PS-specific MBCs at baseline were higher in group A, but they increased significantly only in the groups receiving the booster schedules (groups B and C). PS-specific IgM-only MBCs at baseline positively corelated with the antibody response and the PS-specific swIg MBCs post-immunization. Our findings illustrate the importance of a booster dose for the enrichment of PS-specific immunological memory. IgM-only MBCs and swIg MBCs may serve as additional correlates of vaccine-induced protection.

Cost-Effectiveness Analysis of Routine Childhood Immunization with 20-Valent versus 15-Valent Pneumococcal Conjugate Vaccines in Germany.

This study aimed to evaluate the cost-effectiveness of routine childhood immunization with the 20-valent pneumococcal conjugate vaccine (PCV20) in a four-dose regimen (3 + 1 schedule) versus the 15-valent PCV (PCV15/V114) in a three-dose regimen (2 + 1) in Germany. The study utilized a decision-analytic Markov model to estimate lifetime costs and effectiveness outcomes for a single birth cohort in Germany. The model tracked the incidence of acute pneumococcal infections and long-term pneumococcal meningitis sequelae for both vaccination strategies. The vaccine effectiveness data were derived from published clinical trials and observational studies of PCV7 and PCV13. Indirect effects, such as herd protection and serotype replacement, were included in the model. The model adopted a societal perspective, including direct medical, direct non-medical, and indirect costs. Scenario and sensitivity analyses were performed. In the base case, PCV20 prevented more pneumococcal disease cases and deaths, with an expected gain of 96 quality-adjusted life years (QALYs) compared to V114. However, PCV20 was associated with a total incremental cost of EUR 48,358,424, resulting in an incremental cost-effectiveness ratio (ICER) of EUR 503,620/QALY. Most of the scenario and sensitivity analyses estimated that the ICER for PCV20 exceeded EUR 150,000/QALY. Routine childhood immunization with PCV20 instead of V114 may not be an economically efficient use of healthcare resources in Germany.

Changes in Attitudes towards Influenza and Pneumococcal Vaccination during the Subsiding COVID-19 Pandemic-Results of a Longitudinal Survey Study among Risk Groups in Germany between 2021 and 2023.

BACKGROUND: In many countries, an increase in influenza and pneumococcal vaccination rates was observed during the COVID-19 pandemic. We examined how attitude, risk perception and knowledge towards influenza and pneumococcal vaccines of at-risk patients developed when the COVID-19 pandemic subsided and if COVID-19 vaccination attitude (VA) was still associated with the attitudes towards the two other vaccines. METHODS: We used longitudinal data from two surveys conducted in Germany in 2021 and 2023 among persons with chronic diseases. We assessed VA, risk perception, vaccination knowledge and further psychological determinants of vaccine acceptance. Structural equation modelling using full information maximum likelihood was used to estimate multivariate regressions with planned missing data. RESULTS: Among 543 respondents, the influenza and pneumococcal vaccination rates remained relatively stable between 2021 and 2023. VA also remained unchanged at a moderately positive level, while COVID-19 VA decreased. A constantly positive association between COVID-19 VA and influenza as well as pneumococcal VA was found, independent from a general VA. The perceived danger of influenza increased between 2021 and 2023 and was among the strongest predictors of influenza VA. CONCLUSIONS: Also at the subsiding pandemic, COVID-19 VA was constantly associated with the influenza and pneumococcal VA. It seems sensible to take these aspects into account when designing future vaccination campaigns for at-risk patients. TRIAL REGISTRATION: DRKS00024561. Registered 9 March 2021.

Differences in PCV13 Recommendation Practices between Pediatric Care Providers and Primary Care Providers in China: A Cross-Sectional Survey of Behavior and Social Drivers.

Objectives: This study examines the recommendation behaviors and influencing factors for the 13-valent Pneumococcal Conjugate Vaccine (PCV13) among 3579 Chinese healthcare workers (HCWs), including 1775 pediatric care providers (Peds-PCPs) and 1804 primary care providers (PCPs). Data were collected from May to July 2023 through a national cross-sectional survey using a structured questionnaire, distributed across hospitals providing pediatric services in five provincial-level administrative divisions. Methods: The sociodemographic data, vaccine knowledge, and recommendation practices were analyzed using Pearson's chi-square test, Wilcoxson rank-sum test, and multivariate logistic regression. Results show that while PCPs are more likely to recommend PCV13, vaccine hesitancy persists among Peds-PCPs. Logistic regression revealed that higher influenza vaccination intention, salary, vaccine consultation frequency, familiarity with immunization, work ethic, and flexible schedules positively impacted HCWs' recommendation behavior. Results: Factors influencing Peds-PCPs' recommendations include vaccine training (OR: 1.470, CI: 1.049-2.509), safety recognition (OR: 1.986, CI: 1.163-3.391), concern over rejection (OR = 1.274, CI: 1.076-1.508) and vaccine cost (OR = 1.203, CI: 1.023-1.414). For PCPs, influencing factors were the perceived susceptibility of children to pneumonia (OR = 2.185, CI: 1.074-4.445), acceptance of herd immunity (OR: 1.717, CI: 1.101-2.677), and belief that parents with better family conditions are more likely to accept vaccine recommendations (OR = 1.229, CI: 1.024-1.477). Conclusion: This survey underscores the need for tailored interventions to address differing perceptions and enhance confidence in the safety and efficacy of vaccines among HCWs, particularly Peds-PCPs.

Seizure prophylaxis in pneumococcal meningitis, cohort study.

OBJECTIVE: Our aim was to assess seizure development as a complication of pneumococcal meningitis and its possible prevention with antiseizure medication prophylaxis. METHODS: Antiseizure medication (ASM) prophylaxis has been practiced for a long time at our center. We assessed all cases of community-acquired pneumococcal meningitis admitted from January 2010 to April 2021 recorded in our prospective database and conducted further retrospective studies. RESULTS: Of the 86 cases recorded, 21 (24.4%) developed acute symptomatic seizures, more than half of which (11/21; 52.4%) before admission. Seizure development increased the need for orotracheal intubation and intensive care unit admission, while also lengthening hospital stays and suggesting more risk of death and disability at discharge [adjusted odds ratio (aOR), 3.13; 95% confidence interval (CI): 1-9.8]. Of the 74 patients eligible for ASM prophylaxis, 64 received it and 10 did not. ASM prophylaxis seemed effective in preventing seizure development, as only six seizure events were recorded in 64 patients with ASM prophylaxis (9.4%) compared with four in the 10 patients without prophylaxis (40%). Its preventive capacity was especially notable when administered within 4 h of admission. Differences in mortality did not reach statistical significance. Adverse effects were rare. SIGNIFICANCE: Seizure development is a common complication in pneumococcal meningitis and is associated with increased risks of Intensive Care Unit admission, orotracheal intubation, and longer hospital stays. ASM prophylaxis may be effective in blocking seizure development in patients with preventable seizures and may be associated with better prognosis. Further studies are now warranted. PLAIN LANGUAGE SUMMARY: Infection of the meninges (the covering of the brain) due to the common bacteria S pneumoniae, used to be a fatal disease before the introduction of antibiotics and corticoids. Thanks to these drugs, more people survive this disease but, due to the frequent complications, they may have several sequelae. Seizures are a common complication. Our study suggests that they might be prevented by using antiseizure drugs which may reduce both severity and hospital stay.