Upsurge of pneumococcal clade I-α/CC180 serotype 3 and its association with a LytA mutation linked to immune evasion and disease potential: an observational and experimental study.

Infectious diseases, including invasive pneumococcal disease (IPD) and community‑acquired pneumonia (CAP), are associated with severe burden and adverse outcomes beyond the acute episode. The comprehensive burden has not been previously assessed in Finland. Here, we characterized adult patients (≥ 18years) with IPD and CAP in Finland, followed them up for adverse outcomes, and estimated the economic burden. This is a nationwide registry-based cohort study, including 2894 adults with laboratory-confirmed IPD; 129,203 adults with inpatient CAP; 126,314 adults with outpatient CAP; and their 760,748 age-sex-region-matched controls. Overall, 40-60% of the patients had at least one predefined medical risk factor; however, a substantial proportion (34-40%) of patients aged ≥ 65years did not have any predefined risk factors. Patients aged ≥ 65years with IPD and inpatient CAP had the highest rates of adverse outcomes, including recurrence, admission to institutional care, and acute myocardial infarction. IPD and CAP were associated with considerable attributable healthcare costs, including direct disease-specific costs, increased all-cause costs above them, and indirect costs due to work absenteeism. Serotypes included in the pneumococcal conjugate vaccines (PCVs) PCV13, PCV20, and PCV21 covered 43.0%, 61.1%, and 77.7% of IPD cases, respectively, in the age group ≥ 65years in 2023-2024. IPD and CAP are associated with substantial morbidity, mortality, and economic burden, particularly among adults aged ≥ 65years. In this age group, pneumococcal disease alone accounted for ~€39 million annually in total costs (inflated to 2023 values). As many older patients had no predefined medical risk factors, age‑based pneumococcal vaccination and broader use of higher‑valency conjugate vaccines seem warranted to reduce disease burden and societal costs.

The 21-valent pneumococcal conjugate vaccine (PCV21) covers 83-88% of IPD in US adults but does not include serotype 4 (ST4), which is covered by previously recommended vaccines (PPSV23, PCV15, PCV20). Recent increases in IPD cases due to ST4 have been observed, particularly among adults under 65, including Native American/Alaskan Native and those with social risk factors. As a result, the Advisory Committee on Immunization Practices (ACIP) recommends ST4-containing vaccines (PPSV23, PCV15, and PCV20) for populations with ≥ 30% ST4 IPD cases. In this study, we aimed to analyze ST4 attributable fraction (AF) thresholds for health and economic outcomes of PCV21 versus PCV20 vaccination in US adults aged 19-49 and 50-64 years with underlying medical conditions. We used a validated Markov model to estimate incremental cost-effectiveness ratios (ICERs) for PCV21 versus PCV20 and identified ST4 AF thresholds in which the ICER shifted from 'cost-saving' to 'not cost-effective'. The analysis involved a hypothetical 1 million at-risk adults aged 19-49 and 50-64years. PCV21 remained cost-saving compared to PCV20 when ST4 accounted for ≤ 27% (age 19-49) or ≤ 36% (age 50-64) of IPD. When ST4 increases wereapplied to both IPD and NBPP, these thresholds decreased to ≤ 21% and ≤ 28%, respectively. For populations experiencing moderate increases in the proportion of ST4 (i.e., < 30%), PCV21 may offer health and economic benefits over PCV20 for US adults aged 19-64years with underlying medical conditions. However, in populations with ≥ 30% ST4, ST4-containing vaccines should be used as per ACIP guidance.

Pneumococcal meningitis in children and adults before and after implementation of PCV13 into national pediatric immunization program: A cohort study in Taiwan.

The emergence of vaccine-covered serotypes causing invasive pneumococcal disease (IPD) is a serious concern worldwide. We characterized all national serotype 4 IPD isolates from children and adults received at the Spanish Pneumococcal Reference Laboratory (2009-24). We investigated the unexpected rise of serotype 4 causing IPD in young adults after the COVID-19 pandemic, affecting elderly population in recent years. Epidemiological and genomic analysis confirmed that the rise started as an abrupt cluster of cases in Seville (Andalusia) in the year 2022 due to the ST15063 within GPSC12 lineage. This outbreak initially affected non-vaccinated young individuals associated with high rates of tobacco smoking, alcohol, and inhaled drugs followed by a general distribution through the country in the following years that affected adults ≥ 65 years old. Moreover, ST15063 serotype 4 strains displayed enhanced infection rates of human lung cells that significantly increased in the presence of cigarette smoke exposure and by influenza H3N2 coinfection. These findings highlight the need for targeted vaccination strategies, molecular surveillance, and focused interventions in high-risk populations.

Pneumococcal infections remain a significant public health concern in France, particularly among older adults at higher risk of developing severe forms. In 2023, the French health authorities updated vaccination guidelines recommending a single-dose 20-valent pneumococcal conjugate vaccine (PCV20) for adults at increased risk due to underlying medical conditions and later extending it to all adults aged 65 years and over. The objective of this analysis is first to evaluate the cost-effectiveness and public health impact of PCV20 in replacing 13-valent pneumococcal conjugate vaccine → 23-valent pneumococcal unconjugated polysaccharide vaccine (PCV13 → PPV23) in the vaccination programme and secondly to assess the value of extending the recommendation to a broader population. A deterministic Markov model was adapted to compare clinical and economic outcomes of adult pneumococcal vaccination strategies in France over a lifetime horizon. The economic inputs in this analysis were estimated in 2024 euros from a healthcare system perspective. Population parameters, epidemiological data and cost were derived from French databases and institutional reports. Utility and vaccine effectiveness inputs were obtained from the literature. Replacing PCV13 → PPV23 with PCV20 in at-risk adults reduced pneumococcal disease burden and was a dominant strategy, generating cost savings of €56,786 at the population level (€1.05 per patient) while improving health outcomes with an incremental gain of 0.00015 QALYs per patient. Expanding PCV20 to all individuals aged 65+ further reduced disease incidence and mortality over a lifetime horizon, averting 900 additional invasive pneumococcal diseases (IPD) cases (mainly bacteremia and meningitis), 11,600 pneumonia cases, and over 1,500 deaths. These additional health benefits were achieved at an incremental cost of €63,191 at population level (€0.81 per patient) corresponding to a gain of 0.00019 QALYs per patient. The incremental cost-effectiveness ratio was 4,308 €/QALY, indicating highly cost-effective strategy relative to commonly cited French vaccine HTA benchmarks. PCV20 is a cost-saving alternative to the PCV13 → PPV23 sequence for at-risk adults in France. Expanding recommendations to include all adults aged 65 years and over provides substantial public health gains and represents a highly cost-effective strategy.

Streptococcus pneumoniae asymptomatically colonizes upper respiratory mucosa and invades into deeper tissue through mucosal membrane. Invasive pneumococcal disease has a significantly high rate of mortality, making its control an urgent concern. Mucin is a defensive system against respiratory infection. However, the role of transmembrane mucin against the development of invasive infection has been unclear. In this study, we demonstrate the roles of Muc16 on invasive pneumococcal disease. Muc16 knockout mice had significantly increased bacterial loads in the lungs and brain after nasal pneumococcal challenge, whereas bacterial loads in the nasal cavity had no difference. Under cigarette smoke extract (CSE)-pretreated conditions, they showed increased bacterial loads in the blood with the elevation of serum IL-6 level and a significant increase in the mortality rate. Infiltration of polymorphonuclear leukocytes was suppressed by deficiency of Muc16. The proportion of mucosal disruption in the olfactory epithelium was significantly increased by deficiency of Muc16, and the expression of tight junction molecule ZO-1 was inhibited in CSE-pretreated Muc16 knockout mice. Muc16 is, thus, considered to be essential for preserving the defensive system against pneumococcal translocation from nasal mucosa by regulating inflammatory cell infiltration and mucosal barrier integrity in the upper respiratory tract. MUC16 could be a new target in preventive strategy against pneumococcal infection.IMPORTANCEStreptococcus pneumoniae commonly colonizes the upper respiratory tract without causing symptoms but can sometimes invade deeper tissues and lead to life-threatening diseases, such as pneumonia, bacteremia, and meningitis. The mechanisms that prevent bacteria from spreading beyond the nasal mucosa are still incompletely understood. In this study, we demonstrate that the transmembrane mucin MUC16 plays an important role in protecting against invasive pneumococcal infection. Using a mouse model, we show that loss of Muc16 does not alter nasal colonization but increases bacterial dissemination to systemic organs and worsens survival, particularly under cigarette smoke exposure. Our findings suggest that MUC16 contributes to mucosal defense by maintaining epithelial barrier integrity and supporting neutrophil recruitment at the nasal surface. These results highlight the importance of transmembrane mucins in preventing bacterial invasion and provide new insight into how disruption of mucosal barriers may promote invasive pneumococcal disease.

This was an unusual case of invasive pneumococcal disease in an immunocompetent adult without serious underlying medical conditions. Streptococcus pneumoniae bacteraemia was found with multiple distant sites of infection, including polyarticular septic arthritis, osteomyelitis, multi-level spondylodiscitis, and paravertebral, psoas and pelvic abscesses. A fit and well 56 year old woman presented with a 10 day history of fevers, rigors, and multiple hot, swollen, tender joints. Septic arthritis was initially thought unlikely, but when blood tests showed marked inflammatory response and the patient was febrile, joint aspiration was performed. Streptococcus pneumoniae was grown from blood cultures and aspirates from multiple joints. MRI confirmed distant sites of infection including left sacroiliac joint osteomyelitis, multi-level spondylodiscitis, and small paravertebral, psoas and pelvic abscesses, which were not amenable to drainage. The patient completed 11 weeks of antibiotic therapy, with IV Amoxicillin followed by IV Ceftriaxone, and made a good recovery with full resolution of joint disease. The patient had obesity but was not in a recognised risk group for invasive pneumococcal disease. No underlying medical conditions were found that would predispose her to such widespread infection. Septic arthritis can be polyarticular. Urgent joint aspiration and blood cultures should be undertaken for any patient in whom septic arthritis is considered. Patients with invasive pneumococcal disease should be investigated for predisposing risk factors and should be adequately immunised. This case provides a timely reminder of the virulence of pneumococcus, the severity of invasive pneumococcal disease, and the importance of vaccination.

BackgroundIn Australia, high pneumococcal conjugate vaccine (PCV) coverage has been achieved, yet invasive pneumococcal disease (IPD) continues to cause a significant burden of disease. The epidemiology of IPD was altered by the nonpharmaceutical interventions (NPIs) used to control the coronavirus disease (COVID-19) pandemic. We aimed to analyze this impact on the clinical characteristics associated with IPD in Australian children.MethodWe systematically evaluated the clinical and microbiological characteristics of IPD in children (<18 years) presenting to 4 Australian children's hospitals 2 years before (2017–2018: prepandemic) and after (2021–2022: postpandemic) the implementation of NPIs to mitigate COVID-19. Case counts and proportions were used to compare clinical presentations.ResultsWe identified 220 cases of IPD: 116 in 2017–2018 and 104 in 2021–2022. Causative serotypes were available for 176 cases (80%), with serotype 3 most frequently identified (26% of serotyped IPD, 46/176). One-quarter of cases were due to serotypes included in newer PCVs. Postpandemic cases had a higher proportion of meningitis (13.5% vs 3.4%, P = .001) and test-confirmed associated viral infections (63.8% vs 36.2%, P = .008) compared to prepandemic cases. Children with viral co-infections were significantly more likely to have prolonged fevers (>14 days; 13% vs 1%, P = .001).ConclusionsAlternations in the prevalence of respiratory viral transmission influence the epidemiology and clinical presentation of IPD. Newer PCVs and the implementation of immunization programs that target viral pathogens associated with IPD may reduce the ongoing burden of IPD in children.

To determine the incidence, serotype distribution and clinical outcomes of invasive pneumococcal disease (IPD) in children with acute lymphoblastic leukaemia (ALL) following widespread use of pneumococcal conjugate vaccines (PCVs). Multicentre cohort study. Two tertiary paediatric oncology centres in Australia-Royal Children's Hospital-Melbourne and Perth Children's Hospital. Children with cancer, including a defined subgroup with ALL. All children were assessed for provision of pneumococcal vaccines before and after their diagnosis of cancer. Incidence of IPD in cancer (ALL and non-ALL) compared with the general paediatric population, serotype distribution, vaccination status and clinical outcomes. A total of 29 episodes of IPD in 28 children with cancer were included, of whom 19 had ALL. Less than a quarter had received additional pneumococcal vaccinations beyond the standard PCV schedule. The incidence of IPD in children with ALL was 190-360 times higher than in healthy children (1360 per 100 000 person-years). The majority of episodes (83%) were due to non-PCV13 serotypes, most commonly 23B. Clinical presentation was predominantly bacteraemia. Most patients recovered within 30 days, but there was one death attributable to IPD. Children with ALL remain at substantially increased risk of IPD despite widespread PCV use, with disease largely caused by non-PCV13 serotypes. Uptake of additional pneumococcal doses was low. These findings underscore the need for optimised vaccination and prophylactic strategies in paediatric oncology populations.

Serotype 3 (ST3) Streptococcus pneumoniae remains a major cause of invasive pneumococcal disease and pneumonia despite PCV13 introduction, in part due to potent immune evasion properties. The contribution of the pyruvate metabolic node (SpxB/LctO pathways) to ST3 pathogenesis is poorly defined. We investigated oxygen-dependent fitness, colonization efficiency, and lung pathology in the ST3-strain WU2 and isogenic ΔspxB, ΔlctO, and ΔspxBΔlctO mutants. In vitro growth was assessed under nasopharyngeal (21% O₂) and alveolar (14% O₂) conditions. Murine pneumonia models evaluated survival, bacterial burdens, histopathology, and lung gene expression analyses (RNA-seq and quantitative RT-PCR). ST3-strain exhibited a unique oxygen-sensitive growth defect at 21% O₂, alleviated by spxB deletion, indicating metabolic burden from pyruvate flux. In mice, wild-type WU2 caused severe suppurative bronchopneumonia, alveolar consolidation, hemorrhage, and perivascular inflammation, whereas the ΔspxB mutant showed enhanced distal lung damage, uncontrolled dissemination, and amplified inflammation. Wild-type infection uniquely induced reorganization of bronchial epithelial membranes, forming prominent bacterium-laden bleb-like structures-host-derived membrane protrusions covering intact pneumococci. These structures appeared to be associated with bacterial translocation into tissue without overt cytotoxicity and were largely absent in spxB-deficient mutants despite comparable bacterial colonization densities in the lung. RNA-seq analysis revealed SpxB-dependent reduced expression of T-cell activation (e.g., Rag1 and Themis), consistent with immune sequestration via bleb-like structures. The SpxB-dependent pathway contributes to ST3 pathogenesis through metabolic adaptation and is associated with bleb-like structure formation and altered host immune responses in the lung. These bacterium-laden bleb-like structures represent a novel hallmark mechanism in pneumococcal pathogenesis.

Half a century of pneumococcal vaccination in sickle cell disease: Are we winning the battle or losing immunity?

Coverage and missed opportunities for routine vaccination in adult travellers: a single-centre observational study.

Streptococcus pneumoniae remains a major cause of morbidity and mortality worldwide, especially among children under 5 years of age. The introduction of pneumococcal conjugate vaccines (PCVs) has significantly reduced invasive pneumococcal disease globally. Ghana introduced routine immunization with PCV13 in 2012; however, its impact on pneumococcal carriage at the genomic level remains largely unexplored. This is the first genomic characterization of pneumococcal carriage in Ghana post-PCV13 introduction; in the absence of a matched pre-vaccination genomic dataset, findings are interpreted in the context of the post-vaccination era rather than as a direct pre–post-comparison. We identified substantial genomic diversity among carriage isolates, including 49 Global Pneumococcal Sequence Clusters (GPSCs) and 67 sequence types (STs), of which 21 STs were novel, and 4 were international Pneumococcal Molecular Epidemiology Network clones (Spain9V-3, Greece6B-22, NorwayNT-42 and Sweden15A-25). GPSC 5 (14%) was the most prevalent cluster, followed by GPSC 20 (6%). GPSCs associated with antibiotic resistance (GPSCs 1, 6 and 10) represented 2%, 3% and 2% of isolates, respectively. Importantly, we observed a significant decline in vaccine serotypes (VTs) and a corresponding rise in non-vaccine serotypes (NVTs), notably serotypes 23B and 15BC. Additionally, VTs demonstrated higher levels of antibiotic resistance compared to NVTs (P<0.05). This study provides the first genomic epidemiological insights into pneumococcal populations in Ghana post-PCV13 introduction and underscores the importance of continuous genomic surveillance to monitor serotype replacement and antibiotic resistance trends.

This systematic review aimed to establish if higher-valent conjugate vaccines will provide significantly higher coverage and protection in high-risk groups than the 13-valent pneumococcal conjugate vaccine (PCV13). The PubMed, Science Direct, and Google Scholar search engines were searched for original articles that reported on the type of study, period of the study, high-risk group(s) involved, specimens collected, number of isolates, frequency of serotyped isolates, and serotypes/serogroups of isolates for inclusion. Data from 14 studies based in seven countries, and 789 serotyped/serogrouped isolates, were extracted. There was no significant difference (P = .23) between the frequency of the non-vaccine serotypes (51.6%) and the vaccine serotypes (48.4%). The 23-valent pneumococcal polysaccharide vaccine (PPV23) had the highest serotype coverage (36.5% ± 5.3%) identified among the high-risk groups. The serotype coverage of the vaccines was highest for the cancer group (26.2% to 40.5%) and lowest for the sickle cell disease group (20% to 28.9%). Higher-valent pneumococcal vaccines may provide significantly higher coverage for groups at a high risk of invasive pneumococcal diseases. There is a need to monitor the serotypes associated with high-risk groups.

Community-acquired pneumonia (CAP) remains a leading cause of death globally. Although childhood 13-valent pneumococcal conjugate vaccine (PCV13) has altered the epidemiology of pneumococcal disease in children, risk factors for CAP in older adults remain insufficiently explored. Additionally, few studies have compared risks between those aged 65-74 and ≥ 75 years. We evaluated risk factors for CAP in older Japanese adults by age. We conducted a secondary analysis of data from a multicenter, nationwide case-control study conducted between October 2016 and December 2019. Cases were individuals aged ≥ 65 years with CAP. Up to five controls per case were matched by sex, fiscal-year age, and visit date. Clinical and lifestyle data were questionnaire-based. Adjusted odds ratios (aORs) were calculated for participants overall and stratified by age (65-74 and ≥ 75 years) using conditional logistic regression. Analysis included 142 cases and 596 controls. CAP risk was associated with living with children ≤ 6 years (aOR: 6.15, 95% confidence interval [CI]: 2.84-13.32), low body mass index (BMI) (< 18.5kg/m²) (aOR: 1.78, 95% CI: 1.02-3.09), and impaired activities of daily living (ADL) (aOR: 2.44, 95% CI: 1.12-5.30). High BMI (≥ 25.0kg/m²) was associated with a reduced risk (aOR: 0.55, 95% CI: 0.31-0.95). Among those aged 65-74 years, living with children ≤ 6 years (aOR: 4.89, 95% CI: 1.83-13.08) was a risk factor for CAP, whereas high BMI (aOR: 0.41, 95% CI: 0.18-0.89) and gastrointestinal disease (aOR: 0.19, 95% CI: 0.04-0.84) were associated with a reduced risk. Among those aged ≥ 75 years, chronic obstructive pulmonary disease (aOR: 3.59, 95% CI: 1.29-9.93), asthma (aOR: 2.99, 95% CI: 1.25-7.16), living with children ≤ 6 years (aOR: 11.62, 95% CI: 3.12-43.33), and impaired ADL (aOR: 2.90, 95% CI: 1.10-7.65) were risk factors for CAP. Only living with children ≤ 6 years was significant for pneumococcal CAP (aOR: 7.22, 95% CI: 1.23-42.34). Living with children ≤ 6 years remains a major CAP risk factor in older adults after childhood PCV13 introduction. However, risk factors differ by age. Respiratory comorbidities and functional decline are dominant drivers of CAP in adults aged ≥ 75 years. Prevention strategies should consider age-specific dominant risk factors.

BackgroundAutomated systematic literature review (SLR) may reduce the workload and errors associated with manual review, enabling faster, up-to-date reviews even with increasing publication volumes. Large language models (LLMs) have demonstrated strong capabilities in understanding unstructured languages. However, few studies have explored the potential of a comprehensive LLM platform to streamline the entire SLR process from article screening to data extraction.ObjectiveThis study aimed to investigate the feasibility of applying an LLM-based system to assist with SLR development.MethodsWe developed the Intelligent Systematic Literature Review (ISLaR 2.0) platform, powered by an LLM, and applied it to a use case of the economic burden of pneumococcal disease (PD) literature. First, we established the inclusion and exclusion criteria for the SLR. Second, we defined data elements related to economic burden and domain knowledge, along with guidelines for applying these definitions. Finally, we used the criteria and data element specifications to develop LLM prompts for screening and data extraction. For data extraction, we identified relevant study characteristics and economic burden outcomes. We evaluated ISLaR 2.0’s performance against a gold standard of 50 expert-curated PD articles, using standard metrics (accuracy, precision, recall, and F1-score). We also conducted a qualitative analysis to describe errors made by the system.ResultsISLaR 2.0 performed well in abstract and full-text screening (F1-scores of 86.27 for abstract screening and 87.18 for full-text screening) and data extraction from text (F1-scores of 92.83 for study details and 79.76 for economic burden outcomes). The F1-score for data extraction of tabular economic burden outcome data was 94.83. The qualitative analysis revealed 2 main challenges in extracting economic burden details: misclassification of cost categories and failure to extract relevant information.ConclusionsISLaR 2.0 enabled efficient execution of an SLR regarding the economic burden of PD. The platform allowed users to flexibly define and modify criteria and data elements, supporting its use across a broad range of health research topics.

Young adults at risk of emerging serotype 4 invasive pneumococcal disease vs. other serotypes in Andalusia (Spain), 2022 to 2024: optimising conjugated vaccines strategies.

Incidence of invasive pneumococcal disease (IPD) in American Indian (AI) communities in the Southwest US declined during the COVID-19 pandemic. We estimated the burden and serotype distribution of IPD in the same communities in 2022-24. We conducted active, laboratory-based surveillance for IPD in the Navajo Nation and White Mountain Apache Tribal (WMAT) lands. Isolates were collected and serotyped. Annual incidence rates were calculated and serotype distribution was estimated. The proportion of serotypes covered by available pneumococcal conjugate vaccines (PCV20 and PCV21) were estimated and compared by age group using McNemar's Chi-squared or Exact McNemar tests, as appropriate. IPD rates increased from 2022 to 2024 to pre-pandemic levels; from 45.9 to 62.1 per 100,000 in the Navajo Nation and 52.9 to 84.4 in the WMAT lands. Among adults in the Navajo Nation, serotype 4 accounted for 28.5% of cases and occurred primarily among younger unvaccinated males. The proportion of cases covered by PCV21 was lower than PCV20 for adults 18-49 years (53.2% vs 77.3%; p<0.001) but higher for adults ≥65 years (82.5% vs 65.1%; p=0.03). In the WMAT lands, no cases of serotype 4 were identified; the proportion of cases covered by PCV21 was the same or higher than for PCV20 across age groups. In two AI communities in the Southwest, IPD rates returned to pre-pandemic levels. In the Navajo Nation, the increase was driven by serotype 4 IPD among younger male unvaccinated adults. These findings can inform vaccine recommendations and highlight the value of surveillance.

In Argentina, widespread 13-valent pneumococcal conjugate vaccine (PCV13) use has reshaped pediatric invasive pneumococcal disease (IPD) epidemiology, with ongoing serotype shifts. We assessed IPD burden, clinical and microbiological features, PCV20 coverage, and mortality risk factors. Multicenter prospective observational study based on active surveillance, conducted in 6 pediatric sentinel hospitals (October 2022-September 2025). Children ≤15 years hospitalized with laboratory-confirmed IPD were included. Hospitalization rates per 10,000 discharges were calculated with 95% confidence intervals (CIs). Mortality risk factors were assessed using logistic regression. Among 136,018 hospital discharges, 218 IPD cases were identified (16.0 per 10,000; 95% CI, 14.0-18.3; 0.16% of hospitalizations), with the highest rates in children aged 2-4 years (26.5 per 10,000; 95% CI: 20.6-33.5). Half (45.9%) had underlying conditions. Pneumonia predominated (65.6%), often complicated by pleural effusion/empyema or necrotizing disease, and 18.9% required mechanical ventilation; meningitis occurred in 14.7%. Among 119 serotyped isolates, 30.3% were PCV13, 21.0% additional PCV20 and 48.7% non-PCV20 serotypes, yielding an estimated PCV20 coverage of 51.3%. All isolates were ceftriaxone-susceptible; penicillin resistance (4.6%) was limited to meningitis. Case fatality was 5.0%. In multivariable analysis, sepsis (adjusted odds ratio [aOR] 20.82; 95% CI: 4.23-102.58) and meningitis (aOR 10.75; 95% CI: 2.10-54.95) were strongly associated with mortality. In the late PCV13 era, pediatric IPD in Argentina remains clinically severe and shows marked serotype replacement. PCV20 increases coverage to approximately half of circulating serotypes. Sepsis and meningitis remain key mortality determinants, underscoring the need for early recognition, timely treatment, improved vaccination coverage and continued surveillance to assess PCV20 impact.