Enhancing Immune Response in Non-Small-Cell Lung Cancer Patients: Impact of the 13-Valent Pneumococcal Conjugate Vaccine.

Background: Non-small-cell lung cancer (NSCLC) is one of the most frequently diagnosed diseases among all types of lung cancer. Infectious diseases contribute to morbidity and mortality by delaying appropriate anti-cancer therapy in patients with NSCLC. Methods: The study aimed to evaluate the effectiveness of vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) in 288 newly diagnosed NSCLC patients. The analysis of the post-vaccination response was performed after vaccination by assessing the frequency of plasmablasts via flow cytometry and by assessing the concentration of specific anti-pneumococcal antibodies using enzyme-linked immunosorbent assays. Results: The results of the study showed that NSCLC patients responded to the vaccine with an increase in the frequencies of plasmablasts and antibodies but to a lesser extent than healthy controls. The immune system response to PCV13 vaccination was better in patients with lower-stage NSCLC. We found higher antibody levels after vaccination in NSCLC patients who survived 5 years of follow-up. Conclusions: We hope that our research will contribute to increasing patients' and physicians' awareness of the importance of including PCV13 vaccinations in the standard of oncological care, which will extend the survival time of patients and improve their quality of life.

Anti-SARS-CoV-2 Vaccination and PIMS-TS-Friends or Foe? Case Reports and Literature Review.

Pediatric inflammatory, multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS), also known as a multisystem inflammatory syndrome in children (MIS-C), is diagnosed in children who develop an inadequate inflammatory response after exposure to the SARS-CoV-2 virus. The pathogenesis of the abnormal response of the immune system to a previous SARS-COV-2 infection has not been explained. Similarly, the safety and effectiveness of COVID-19 vaccinations in this group of patients have become the subject of clinical discussion. Presenting experiences from many centers aims to answer this question. We present 4 cases of patients who suffered from PIMS-TS. Three of them were safely vaccinated against COVID-19 after illness. One patient developed PIMS-TS temporarily associated with COVID-19 vaccination. We also collected and discussed data from other centers.

DOCK8 Mutation in Patient with Juvenile Idiopathic Arthritis and Sjögren's Syndrome.

This study investigated the association between autoimmunity and immunodeficiency in pediatric patients, focusing on the case of a 15-year-old female diagnosed with juvenile idiopathic arthritis (JIA) and secondary Sjögren's syndrome. The patient presented with a variety of symptoms, including joint pain, bronchial asthma, leukopenia, and skin lesions. Genetic testing revealed a de novo mutation in the DOCK8 gene, associated with DOCK8 deficiency, a condition usually associated with immunodeficiencies. The clinical course, diagnostic pathway, and treatment history are detailed, highlighting the importance of molecular diagnostics in understanding the genetic basis of rheumatic diseases. This case highlights the need to consider innate immune errors in patients with multiple diseases or atypical symptoms of rheumatic diseases. Furthermore, the study highlights the importance of targeted treatment, including genetic counseling, to improve patient outcomes. The observed association between autoimmunity and immune deficiency reinforces the importance of molecular testing in elucidating the causes of previously idiopathic rheumatic diseases, contributing to improved patient care and quality of life.

How Can Selected Dietary Ingredients Influence the Development and Progression of Endometriosis?

Endometriosis is a chronic, hormone-dependent disease characterized by the presence of endometrial tissue in ectopic locations. Since the treatment options for this disease are still limited, and the cure rate is unsatisfactory, the search for ways to treat symptoms and modify the course of the disease is of key importance in improving the quality of life of patients with endometriosis. So far, the literature has shown that nutrition can influence endometriosis through hormonal modification and altering the inflammatory or oxidative response. Since the importance of nutrition in this disease is still a subject of scientific research, we aimed to summarize the current knowledge on the role of dietary modifications in endometriosis. Our review showed that nutrients with anti-inflammatory and antioxidant properties, including most vitamins and several trace elements, may influence the pathogenesis of endometriosis and can be considered as the nutrients preventing the development of endometriosis. However, despite the many discoveries described in this review, further interdisciplinary research on this topic seems to be extremely important, as in the future, it may result in the development of personalized therapies supporting the treatment of endometriosis.

The Relationship between Cancer Stage, Selected Immunological Parameters, Epstein-Barr Virus Infection, and Total Serum Content of Iron, Zinc, and Copper in Patients with Laryngeal Cancer.

(1) Background: the purpose of the study was to assess the relationship between cancer stage, selected immunological parameters, Epstein-Barr virus (EBV) infection, and total serum content of iron, zinc, and copper in patients with laryngeal cancer (LC). (2) Methods: serum Fe, Zn, and Cu were measured in 40 LC patients and 20 controls. Immunophenotyping of peripheral blood lymphocytes was performed by flow cytometry using fluorescent antibodies against CD3, CD4, CD8, CD19, CD25, CD69, and PD-1. Tumor and lymph node lymphocytes were analyzed by flow cytometry. EBV DNA was quantified by real-time PCR, targeting the EBNA-1 gene. Associations between serum elements, immune markers, and cancer grade/stage were evaluated using ANOVA and appropriate nonparametric tests. (3) Results: levels of Fe, Cu, and Zn were lower, while Cu/Zn was statistically higher, in patients with LC than in the control group. Correlation analysis showed a statistically significant association between the levels of these elements and parameters of the TNM (Tumor, Node, Metastasis) staging system, immunophenotype, and the amount of EBV genetic material in patients with LC who survived for more than 5 years. (4) Conclusion: the results suggest that the total serum levels of the determined micronutrients may significantly affect the immunopathogenesis and progression of LC.

How Can Imbalance in Oral Microbiota and Immune Response Lead to Dental Implant Problems?

Dental implantology is one of the most dynamically developing fields of dentistry, which, despite developing clinical knowledge and new technologies, is still associated with many complications that may lead to the loss of the implant or the development of the disease, including peri-implantitis. One of the reasons for this condition may be the fact that dental implants cannot yield a proper osseointegration process due to the development of oral microbiota dysbiosis and the accompanying inflammation caused by immunological imbalance. This study aims to present current knowledge as to the impact of oral microflora dysbiosis and deregulation of the immune system on the course of failures observed in dental implantology. Evidence points to a strong correlation between these biological disturbances and implant complications, often stemming from improper osseointegration, pathogenic biofilms on implants, as well as an exacerbated inflammatory response. Technological enhancements in implant design may mitigate pathogen colonization and inflammation, underscoring implant success rates.

Immune Checkpoint Pathway Expression in Lymphocyte Subpopulations in Patients with Common Variable Immunodeficiency and Chronic Lymphocytic Leukemia.

This study aims to gain a deeper understanding of chronic lymphocytic leukemia (CLL) and common variable immunodeficiency (CVID) by studying immune cells and specific immune checkpoint signaling pathways. The analysis of the percentage of selected immune points and their ligands (PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200) on peripheral blood lymphocyte subpopulations was performed using flow cytometry, and additional analyses determining the serum concentration of the above-mentioned molecules were performed using enzyme immunoassay tests. The obtained results indicate several significant changes in the percentage of almost all tested molecules on selected subpopulations of T and B lymphocytes in both CVID and CLL patients in relation to healthy volunteers and between the disease subunits themselves. The results obtained were also supported by the analysis of the serum concentration of soluble molecules tested. By uncovering valuable insights, we hope to enhance our comprehension and management of these conditions, considering both immunodeficiencies and hematological malignancies. Understanding the role of these signaling pathways in disease development and progression may lead to the development of modern, personalized diagnostic and therapeutic strategies. Ultimately, this knowledge may enable the monitoring of the immune system in patients with CVID and CLL, paving the way for improved patient care in the future.

Exploring the Significance of Immune Checkpoints and EBV Reactivation in Antibody Deficiencies with Near-Normal Immunoglobulin Levels or Hyperimmunoglobulinemia.

This study delves into the intricate landscape of primary immunodeficiencies, with a particular focus on antibody deficiencies characterized by near-normal immunoglobulin levels or hyperimmunoglobulinemia. Contrary to the conventional focus on genetic dysregulation, these studies investigate the key roles of immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, on selected subpopulations of T and B lymphocytes and their serum concentrations of soluble forms in patients recruited for the studies in healthy volunteers. In addition, the studies also show the role of Epstein-Barr virus (EBV) reactivation and interactions with tested pathways of immune checkpoints involved in the immunopathogenesis of this disease. By examining the context of antibody deficiencies, this study sheds light on the nuanced interplay of factors beyond genetics, particularly the immune dysregulations that occur in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical presentation of patients and may contribute to the development of cancer in the future, especially related to hematological malignancies.

How Toll-like Receptor 9 Plays a Key Role in the Development of Gastric Cancer and Is Linked to Epstein-Barr Virus Infection.

The relationship between Toll-like receptor 9 (TLR-9) signaling and its involvement with Epstein-Barr virus (EBV) in gastric cancer (GC) is complex and currently under study. This research intended to understand TLR-9's role in certain T and B lymphocytes and the serum levels of TLR-9 in GC patients versus healthy subjects. The team explored links between these immune markers and various GC traits, such as histological grade, tumor progression stages, cancer types, and survival rates. Additionally, the research sought to find if EBV genetic material influences these immune reactions. Using flow cytometry, TLR-9 levels in different immune cells were analyzed. At the same time, the amount of TLR-9 in the serum was determined. The results showed GC patients had varied TLR-9 levels compared to healthy subjects, with specific cells showing noticeable changes. When grouped by GC attributes, key relationships emerged between TLR-9 amounts, the histological grade, progression stages, and cancer types. A notable finding was the connection between TLR-9 levels and EBV genetic presence, suggesting possible interactions between TLR-9 responses and EBV-related GC processes. Survival data also hinted at TLR-9's potential as a predictor linked to clinical traits. Overall, this research emphasizes TLR-9's complex role in GC's immune responses, pinpointing its interactions with particular cells, clinical features, and EBV. The study unveils a complex web affecting GC and paves the way for new treatment avenues targeting TLR-9 pathways.

Could Immune Checkpoint Disorders and EBV Reactivation Be Connected in the Development of Hematological Malignancies in Immunodeficient Patients?

Primary immunodeficiencies (PIDs) and secondary immunodeficiencies (SIDs) are characterized by compromised immune function, rendering individuals susceptible to infections and potentially influencing cancer development. Epstein-Barr virus (EBV), a widespread herpesvirus, has been linked to cancer, particularly in those with weakened immune systems. This study aims to compare selected immune parameters, focusing on immune checkpoint molecules (PD-1/PD-L1, CTLA-4/CD86, CD200R/CD200), and EBV reactivation in patients with chronic lymphocytic leukemia (CLL, a representative of SIDs) and common variable immunodeficiency (CVID, a representative of PIDs). We performed a correlation analysis involving patients diagnosed with CLL, CVID, and a healthy control group. EBV reactivation was assessed using specific antibody serology and viral load quantification. Peripheral blood morphology, biochemistry, and immunophenotyping were performed, with emphasis on T and B lymphocytes expressing immune checkpoints and their serum concentrations. Our findings revealed elevated EBV reactivation markers in both CLL and CVID patients compared with healthy controls, indicating increased viral activity in immunodeficient individuals. Furthermore, immune checkpoint expression analysis demonstrated significantly altered percentages of T and B lymphocytes expressing PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200 in CLL and CVID patients. This suggests a potential interplay between immune checkpoint dysregulation and EBV reactivation in the context of immunodeficiency. In conclusion, our study underscores the intricate relationship between immune dysfunction, EBV reactivation, and immune checkpoint modulation in the context of immunodeficiency-associated cancers. The altered expression of immune checkpoints, along with heightened EBV reactivation, suggests a potential mechanism for immune evasion and tumor progression. These findings provide insights into the complex interactions that contribute to cancer development in immunocompromised individuals, shedding light on potential therapeutic targets for improved management and treatment outcomes. Further investigations are warranted to elucidate the underlying mechanisms and to explore potential interventions to mitigate cancer risk in these patient populations.

In the Search for Biomarkers of Pulmonary Arterial Hypertension, Are Cytokines IL-2, IL-4, IL-6, IL-10, and IFN-Gamma the Right Indicators to Use?

Pulmonary arterial hypertension (PAH) is a complex disorder characterized by increased pressure in the pulmonary arteries, leading to right heart failure. While the exact mechanisms underlying PAH are not fully understood, cytokines have been implicated in the pathogenesis of the disease. Cytokines play a crucial role in regulating immune responses and inflammation. These small proteins also play a key role in shaping the immunophenotype, which refers to the specific characteristics and functional properties of immune cells, which can have a significant impact on the development of PAH. The aim of this study was to determine the immunophenotype and the concentration of selected cytokines, IL-2, IL-4, IL-6, IL-10, and IFN-gamma, in patients diagnosed with PAH (with particular emphasis on subtypes) in relation to healthy volunteers. Based on the obtained results, we can conclude that in patients with PAH, the functioning of the immune system is deregulated as a result of a decrease in the percentage of selected subpopulations of immune cells in peripheral blood and changes in the concentration of tested cytokines in relation to healthy volunteers. In addition, a detailed analysis showed that there are statistically significant differences between the PAH subtypes and the tested immunological parameters. This may indicate a significant role of the immune system in the pathogenesis of PAH.

Unraveling the Role of Toll-like Receptors in the Immunopathogenesis of Selected Primary and Secondary Immunodeficiencies.

The human immune system is a complex network of cells, tissues, and molecules that work together to defend the body against pathogens and maintain overall health. However, in some individuals, the immune system fails to function correctly, leading to immunodeficiencies. Immunodeficiencies can be classified into primary (PID) and secondary (SID) types, each with distinct underlying causes and manifestations. Toll-like receptors (TLRs), as key components of the immune system, have been implicated in the pathogenesis of both PID and SID. In this study, we aim to unravel the intricate involvement of TLR2, TLR4, TLR3, TLR7, TLR8, and TLR9 in the immunopathogenesis of common variable immunodeficiency-CVID (as PID)-and chronic lymphocytic leukemia-CLL (as SID). The obtained results indicate a significant increase in the percentage of all tested subpopulations of T lymphocytes and B lymphocytes showing positive expression of all analyzed TLRs in patients with CVID and CLL compared to healthy volunteers, constituting the control group, which is also confirmed by analysis of the concentration of soluble forms of these receptors in the plasma of patients. Furthermore, patients diagnosed with CVID are characterized by the percentage of all lymphocytes showing positive expression of the tested TLR2, TLR4, TLR3, and TLR9 and their plasma concentrations in relation to patients with CLL. By investigating the functions and interactions of TLRs within the immune system, we seek to shed light on their critical role in the development and progression of these immunodeficiencies. Through a comprehensive analysis of the literature and presented experimental data, we hope to deepen our understanding of the complex mechanisms by which TLRs contribute to the pathogenesis of PID and SID. Ultimately, our findings may provide valuable insights into developing targeted therapeutic strategies to mitigate the impact of these disorders on those affected by immunodeficiency.

The Crossroads of the Coagulation System and the Immune System: Interactions and Connections.

The coagulation and immune systems, two vital systems in the human body, share intimate connections that fundamentally determine patient health. These systems work together through several common regulatory pathways, including the Tissue Factor (TF) Pathway. Immune cells expressing TF and producing pro-inflammatory cytokines can influence coagulation, while coagulation factors and processes reciprocally impact immune responses by activating immune cells and controlling their functions. These shared pathways contribute to maintaining health and are also involved in various pathological conditions. Dysregulated coagulation, triggered by infection, inflammation, or tissue damage, can result in conditions such as disseminated intravascular coagulation (DIC). Concurrently, immune dysregulation may lead to coagulation disorders and thrombotic complications. This review elucidates these intricate interactions, emphasizing their roles in the pathogenesis of autoimmune diseases and cancer. Understanding the complex interplay between these systems is critical for disease management and the development of effective treatments. By exploring these common regulatory mechanisms, we can uncover innovative therapeutic strategies targeting these intricate disorders. Thus, this paper presents a comprehensive overview of the mutual interaction between the coagulation and immune systems, highlighting its significance in health maintenance and disease pathology.

Maternal Serum Angiogenic Profile and Its Correlations with Ultrasound Parameters and Perinatal Results in Normotensive and Preeclamptic Pregnancies Complicated by Fetal Growth Restriction.

FGR is a complication of pregnancy in which the fetus does not reach its programmed growth potential due to placental reasons and it is the single largest risk factor of stillbirth. Babies with FGR are at increased risk of mortality and morbidity not only in the perinatal period, but also in later life. FGR presents a huge challenge for obstetricians in terms of its detection and further monitoring of pregnancy. The ultrasound is the gold standard here; apart from assessing fetal weight, it is used to measure Doppler flows in maternal and fetal circulation. It seems that additional tests, like biochemical angiogenic factors measurement would be helpful in diagnosing FGR, identifying fetuses at risk and adjusting the surveillance model. The study aimed to assess the potential relationship between the concentration of sEng, sFlt-1, PlGF, and the sFlt-1/PlGF ratio in maternal serum at delivery and maternal and fetal Doppler flow measurements as well as perinatal outcomes in pregnancies complicated by FGR with and without PE, isolated PE cases and normal pregnancies. The use of angiogenic markers is promising not only in PE but also in FGR. Numerous correlations between ultrasound and Doppler studies, perinatal outcomes and disordered angiogenesis marker levels in maternal serum suggest that biochemical parameters have a great potential to be used as a complementary method to diagnose and monitor pregnancies with FGR. The, PlGF in particular, could play an outstanding role in this regard.

How Do Microorganisms Influence the Development of Endometriosis? Participation of Genital, Intestinal and Oral Microbiota in Metabolic Regulation and Immunopathogenesis of Endometriosis.

Microorganisms inhabiting the human body play an extremely key role in its proper functioning, as well as in the development of the immune system, which, by maintaining the immune balance, allows you to enjoy health. Dysbiosis of the intestinal microbiota, or in the oral cavity or reproductive tract, understood as a change in the number and diversity of all microorganisms inhabiting them, may correlate with the development of many diseases, including endometriosis, as researchers have emphasized. Endometriosis is an inflammatory, estrogen-dependent gynecological condition defined by the growth of endometrial cells outside the uterine cavity. Deregulation of immune homeostasis resulting from microbiological disorders may generate chronic inflammation, thus creating an environment conducive to the increased adhesion and angiogenesis involved in the development of endometriosis. In addition, research in recent years has implicated bacterial contamination and immune activation, reduced gastrointestinal function by cytokines, altered estrogen metabolism and signaling, and abnormal progenitor and stem cell homeostasis, in the pathogenesis of endometriosis. The aim of this review was to present the influence of intestinal, oral and genital microbiota dysbiosis in the metabolic regulation and immunopathogenesis of endometriosis.

How Do Minerals, Vitamins, and Intestinal Microbiota Affect the Development and Progression of Heart Disease in Adult and Pediatric Patients?

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, far ahead of cancer. Epidemiological data emphasize the participation of many risk factors that increase the incidence of CVDs, including genetic factors, age, and sex, but also lifestyle, mainly nutritional irregularities and, connected with them, overweight and obesity, as well as metabolic diseases. Despite the importance of cardiovascular problems in the whole society, the principles of prevention of CVDs are not widely disseminated, especially among the youngest. As a result, nutritional neglect, growing from childhood and adolescence, translates into the occurrence of numerous disease entities, including CVDs, in adult life. This review aimed to draw attention to the role of selected minerals and vitamins in health and the development and progression of CVDs in adults and children. Particular attention was paid to the effects of deficiency and toxicity of the analyzed compounds in the context of the cardiovascular system and to the role of intestinal microorganisms, which by interacting with nutrients, may contribute to the development of cardiovascular disorders. We hope this article will draw the attention of society and the medical community to emphasize promoting healthy eating and proper eating habits in children and adults, translating into increased awareness and a reduced risk of CVD.

Root Canal Infection and Its Impact on the Oral Cavity Microenvironment in the Context of Immune System Disorders in Selected Diseases: A Narrative Review.

The oral cavity has a specific microenvironment, and structures such as teeth are constantly exposed to chemical and biological factors. Although the structure of the teeth is permanent, due to exposure of the pulp and root canal system, trauma can have severe consequences and cause the development of local inflammation caused by external and opportunistic pathogens. Long-term inflammation can affect not only the local pulp and periodontal tissues but also the functioning of the immune system, which can trigger a systemic reaction. This literature review presents the current knowledge on root canal infections and their impact on the oral microenvironment in the context of immune system disorders in selected diseases. The result of the analysis of the literature is the statement that periodontal-disease-caused inflammation in the oral cavity may affect the development and progression of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, or Sjogren's syndrome, as well as affecting the faster progression of conditions in which inflammation occurs such as, among others, chronic kidney disease or inflammatory bowel disease.

Immunomodulatory Role of Interferons in Viral and Bacterial Infections.

Interferons are a group of immunomodulatory substances produced by the human immune system in response to the presence of pathogens, especially during viral and bacterial infections. Their remarkably diverse mechanisms of action help the immune system fight infections by activating hundreds of genes involved in signal transduction pathways. In this review, we focus on discussing the interplay between the IFN system and seven medically important and challenging viruses (herpes simplex virus (HSV), influenza, hepatitis C virus (HCV), lymphocytic choriomeningitis virus (LCMV), human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), and SARS-CoV coronavirus) to highlight the diversity of viral strategies. In addition, the available data also suggest that IFNs play an important role in the course of bacterial infections. Research is currently underway to identify and elucidate the exact role of specific genes and effector pathways in generating the antimicrobial response mediated by IFNs. Despite the numerous studies on the role of interferons in antimicrobial responses, many interdisciplinary studies are still needed to understand and optimize their use in personalized therapeutics.

Possible Correlation between Urocortin 1 (Ucn1) and Immune Parameters in Patients with Endometriosis.

The etiology of endometriosis (EMS) has not been clearly elucidated yet, and that is probably the reason why its diagnostic process is frequently long-lasting and inefficient. Nowadays, the non-invasive diagnostic methods of EMS are still being sought. Our study aimed to assess the serum and peritoneal fluid levels of urocortin 1 (Ucn1) in patients with EMS and healthy women. Moreover, considering the immune background of the disease, the association between Ucn1 and several immune parameters was studied in both groups. We found that the serum Ucn1 level was significantly upregulated in women with EMS compared to healthy patients. Moreover, higher serum Ucn1 levels tended to correspond with more advanced stages of the disease (p = 0.031). Receiver operating characteristic (ROC) analysis revealed that based on serum Ucn1 levels, it is possible to distinguish deep infiltrating endometriosis (DIE) from among other EMS types. Together, these results indicate Ucn1 as a possible promising biomarker of EMS: however, not in isolation, but rather to enhance the effectiveness of other diagnostic methods.

The Molecular Epidemiology of Pneumococcal Strains Isolated from the Nasopharynx of Preschool Children 3 Years after the Introduction of the PCV Vaccination Program in Poland.

The genetic mechanisms of resistance, clonal composition, and the occurrence of pili were analyzed in 39 pneumococcal strains isolated from healthy children in the southeastern region of Poland. Strains with resistance to combinations of erythromycin, clindamycin, and tetracycline were found in clonal groups (CGs) related to Tennessee 23F-4 and Taiwan 19F-14 clones. Capsular switching possibly occurred in the Spain 9V-3 clone and its variants to serotypes 35B and 6A, as well as DLVs of Tennessee 23F-4 to serotype 23A. The double-locus variants of Colombia 23F-26 presented serotype 23B. The major transposons carrying the erythromycin and tetracycline resistance genes were Tn6002 (66.6%), followed by Tn916 (22.2%) and Tn2009 (11.1%). The macrolide efflux genetic assembly (MEGA) element was found in 41.7% of all erythromycin-resistant isolates. The majority of the isolates carrying the PI-1 gene belonged to the CGs related to the Spain 9V-3 clone expressing serotypes 35B and 6A, and the presence of both PI-1 and PI-2 was identified in CG4 consisting of the isolates related to the Taiwan 19F-14 clone expressing serotypes 19F and 19A. Importantly, in the nearest future, the piliated strains of serogroups 23B, 23A, and 35B may be of concern, being a possible origin of the emerging clones of piliated non-vaccine pneumococcal serotypes in Poland. This study reveals that nasopharyngeal carriage in children is an important reservoir for the selection and spreading of new drug-resistant pneumococcal clones in the community after the elimination of vaccine serotypes.