PCV13 Vaccination Research Articles

Interim Results of a Prospective Trial Testing Vaccination Against Pneumococcus before and after CD19 CAR T Cell Therapy to Optimize Humoral Immunity

Background CD19 targeted CAR T cell therapy (CAR-T) can lead to B cell aplasia, and CAR-T patients often have few protective antibodies (Abs) against polysaccharide antigens such as Streptococcus pneumoniae (Walti et al, JCI Insight, 2021). We previously reported that vaccinating CAR-T patients with PCV13, pneumococcal 13-valent conjugate vaccine, did not induce humoral protection when given at 3- or 6-months post therapy (Lee et al, EBMT, 2021). Subsequently, some patients developed humoral protection following vaccination at day+360 or maintained seroprotective IgG Abs present at baseline. Here we present interim results of a Simons two-stage design phase II trial (NCT04745559) testing the hypothesis that PCV13 given before and after CAR-T will induce humoral protection against pneumococcus among CAR-T patients. Method Eligible patients were ≥18 years old with large B cell lymphoma (LBCL) and under consideration for CAR-T. All patients received PCV13 7 days (range, 4-21) before apheresis and again at day+30 (range, 21-37) and day+90 (range, 75-115) post infusion. Pre- and post-serum pneumococcal IgG Abs were drawn to assess humoral response. Pneumococcal serotypes tested include those specific (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F) and non-specific (8, 9N, 12F) to PCV13 vaccine. An established serotype specific IgG concentration ≥1.3µg/mL was considered protective, and a patient with ≥6/11 tested vaccine specific serotypes meeting this threshold was deemed to have long-term humoral protection against pneumococcus. Descriptive analysis was conducted for patient characteristics and paired nonparametric t-test was performed to compare absolute IgG Abs between pre-and post-vaccination timepoints. Results As of 7/01/2022, 7 enrolled patients were evaluable for immune response to vaccine. Median age was 65 (range, 43-75). Four patients received prior autologous stem cell transplant and had history of PCV vaccination. At baseline, only 1 out of 7 patients met the criteria of humoral protection. Three patients had CD19+ B cell count ≤5 cells/ul, and 1 patient had IgG level <400mg/dl. Seven patients received the first PCV13 before apheresis. Out of 6 patients, who did not have humoral protection at baseline, 2 patients achieved humoral protection prior to the start of conditioning chemotherapy. The patient with humoral protection at baseline had vaccine specific IgG Abs remain similar between these timepoints (P=0.99). One patient withdrew from the study before day+30, after developing ICANS grade 3. Six patients proceeded to receive the second dose of PCV13, 5 with paired Abs at day+30 and day+90. Two patients who achieved humoral protection with the first vaccine maintained humoral protection at day+30, and one of them subsequently lost protection at day+90. Three patients who did not have humoral protection since baseline did not mount humoral protection at day+90, after the second vaccine was administered at day+30. Before day+90, 1 patient contracted COVID infection and did not receive the third vaccine. Five patients proceeded to receive the third PCV13 at day+90, and of these patients, 3 patients had paired Abs at day+90 and day+180. One patient who achieved humoral protection with the first vaccine and lost the immunity at day+90 successfully achieved humoral protection again with the third vaccine (Figure 1). Patients’ clinical characteristics and laboratory values are presented in Table 1. As compared to other subjects, Subject 001 who responded to the first and third vaccine had CD19+ B cells prior to CAR-T and recovery of CD19+ B cells at day+180. There were no adverse events related to PCV13. Conclusion Interim results from this prospective clinical trial demonstrate that few LBCL patients had humoral protection against pneumococcus at baseline. Some patients responded to PCV13 given prior to CAR-T, and the immunity was maintained post CAR-T. PCV13 did not induce humoral protection when given at day+30, but one patient who responded to the first vaccine successfully achieved humoral protection again with the vaccine given at day+90. This patient's characteristics were notable for CD19+ B cells present prior to CAR-T and recovered at day+180. PCV13 vaccine was well tolerated in all patients enrolled in this trial. Additional biomarker analysis is ongoing including evaluation for cellular immune response against the vaccine adjuvant. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immunogenicity of the Currently Recommended Pneumococcal Vaccination Schedule in Patients with Chronic Lymphocytic Leukaemia

Background Patients with chronic lymphocytic leukemia (CLL) are at increased risk of both invasive pneumococcal disease (IPD) and community acquired pneumonia (CAP) caused by Streptococcus pneumoniae. Therefore, international guidelines recommend pneumococcal vaccination for all CLL patients, preferably before initiation of treatment. The vaccination schedule recommended in the European Conference on Infections in Leukaemia (ECIL) 7 guideline consists of Prevnar13®, a 13-valent pneumococcal conjugated vaccine (PCV13) followed 2 months later by Pneumovax23®, a 23-valent polysaccharide vaccine (PPSV23). However, the immunogenicity of this sequential pneumococcal vaccination schedule in CLL patients is unknown. The aim of this study is to assess the immunogenicity of PCV13 followed by PPSV23 in untreated and treated CLL patients, as CLL treatment has been shown to be a major determinant of COVID-19 vaccine immunogenicity. Methods We quantified pneumococcal immunoglobulin G (IgG) concentrations to 5 pneumococcal serotypes shared across both vaccines (6B, 9V, 14, 19F, 23F) and 4 serotypes unique to PPSV23 (8, 15B, 20, 33F) before and 4-8 weeks after vaccination using a validated multiplex immunoassay, Luminex®. The primary outcome was the serologic response rate (SRR), defined as a ≥4-fold increase in ≥70% of the serotype-specific anti-pneumococcal IgGs. Secondary outcome was serologic protection, defined as an antibody concentration of ≥1.3 mcg/ml for ≥70% of all measured serotypes, in accordance with the definition by the American Academy of Allergy, Asthma & Immunology. Additional secondary outcomes were serotype-specific serologic protection and IgG level dynamics. Results We included 113 CLL patients (mean age 66 years; 39/113 female) in one academic and six teaching hospitals in the Netherlands. All completed the vaccination and measurement schedule. Median time since CLL diagnosis was 3.6 years. Of the 113 patients 33 had previously received CLL treatment, including rituximab (22 patients), cytotoxic chemotherapy (11), ibrutinib (10) and/or venetoclax (7). Seven patients received intravenous immunoglobulin prior to the vaccinations, while 6 received this during the vaccination scheme. The SRR was 11.5% (15% in untreated and 3% in treated patients) (Table 1). A statistically significant increase in all serotype-specific antibody concentrations was observed after vaccination (p <0.001) (Figure 1). The immunogenicity varied per serotype: the percentage of patients mounting a 4-fold increase was lowest for serotype 20 (16%) and highest for serotype 9V (40%). The serotype-specific anti-pneumococcal IgGs after vaccination were all significantly lower in treated than in previously untreated patients. Nevertheless, treatment status was not statistically significant associated with the SRR. Total IgG concentration prior to vaccination was the only evaluated factor associated with the SRR (OR 5.69; p = 0.008). Serologic protection increased from 1.8% before vaccination to 10.6% after both vaccinations (13.8% in untreated and 3% in treated patients). Serotype-specific protection was highest for serotype 14 and 33F (43.4% of patients obtained a concentration of ≥1.3 mcg/ml) and lowest for serotype 6B (16.8%). Conclusion The serologic response to combined PCV13 and PPSV23 vaccination is impaired in previously treated CLL patients as well as in treatment-naive patients, a contrast with COVID-19 vaccination. These findings emphasize the importance of further investigation into the pneumococcal vaccination response in CLL patients. Since patients with CLL are insufficiently protected after a single dose of PCV13, research should focus on multi-dose PCV schedules with the currently available higher valent T cell dependent conjugate vaccines. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Invasive pneumococcal infections in France: Changes from 2009 to 2021 in antibiotic resistance and serotype distribution of Streptococcus pneumoniae based on data from the French Regional Pneumococcal Observatories network

ObjectiveThe 23 French Regional Pneumococcal Observatories (ORPs) analyzed antibiotic resistance and serotypes of Streptococcus pneumoniae strains isolated from invasive infections in France over a 12-year period. MethodsBetween 2009 and 2021, the ORPs analyzed 19,319 strains, including 1,965 in children and 17,354 in adults. Strains were assessed for their resistance to penicillin G, amoxicillin and cefotaxime. Serotypes were identified in collaboration with the National Reference Centre. ResultsDuring this period, the number of strains collected yearly decreased significantly. The decrease was particularly pronounced up until 2013, especially in children (-61.0%). However, penicillin non-susceptible strains (PNSPs) increased in children (24.7% in 2009 vs 45.0% in 2021, p < 0.0001) and in adults (27.1% in 2009 vs 31.3% in 2021, p < 0.05), as well as resistance (I + R) to amoxicillin (children: 12.5% in 2009 vs 19.4% in 2021, p < 0.05; adults: 13.4% in 2009 vs 14.5% in 2021, NS) and resistance (I + R) to cefotaxime (children: 8.0% in 2009 vs 13.1% in 2021, p < 0.05; adults: 7.1% in 2009 vs 11.9% in 2021, p < 0.0001). All in all, the proportion of strains belonging to serotypes present in the PCV13 vaccine has fallen sharply, from 64.8% in 2009 to 23.6 % in 2021. At the same time, serotypes such as 8, 10A, 11A, 15B/C and 9N, not included in PCV13, were increasing. ConclusionDuring the study period, data collected by the network highlighted an increase of invasive PNSPs in children and non-vaccine serotypes. Surveillance of resistance and serotypes remains instrumental, particularly to monitor the evolution of vaccine efficacy.

Caregiver Willingness to Vaccinate Children with Pneumococcal Vaccines and to Pay in a Low-Resource Setting in China: A Cross-Sectional Study.

To determine the vaccine hesitancy of pneumococcal conjugate vaccines (PCVs) in a low-resource setting in China and to identify associated factors, a face-to-face questionnaire survey was conducted in the city of Guilin, China, from December 2021 to March 2022, which comprised sociodemographic information, attitudes toward vaccines and pneumonia, and PCV13 vaccination willingness and willingness to pay (WTP). Stepwise logistic regression and Tobit regression models were fitted to identify factors associated with PCV13 vaccination willingness and WTP, respectively. In total, 1254 questionnaires were included, of which 899, 254, and 101 participants showed acceptance, hesitancy, and refusal to vaccinate their children with PCV13, respectively. Only 39.07% of participants knew about PCV13 before this survey. A total of 558 (48.40%) participants accepted the full payment of vaccination, and 477 (41.37%) other participants accepted the partial payment, with a median cost of CNY 920.00. Demographics, social and psychological context, and attitudes toward vaccines were all associated with PCV13 vaccination but varied for hesitators and refusers. There is a substantial local demand for vaccinating children with PCV13 and partial payment is widely accepted. More publicity and educational efforts and a socially supportive environment are required to alleviate vaccine hesitancy.

Kawasaki Disease Following the 13-valent Pneumococcal Conjugate Vaccine and Rotavirus Vaccines.

Temporal associations between Kawasaki disease (KD) and childhood vaccines have been reported. Limited data on KD following 13-valent pneumococcal conjugate (PCV13) and rotavirus vaccines are available. We conducted a self-controlled risk interval study using Vaccine Safety Datalink electronic health record data to investigate the risk of KD following PCV13 and rotavirus vaccines in children <2 years of age who were born from 2006 to 2017. All hospitalized KD cases identified by International Classification of Diseases diagnosis codes that fell within predefined risk (days 1-28 postvaccination) and control (days 29-56 for doses 1 and 2, and days 43-70 for doses 3 and 4) intervals were confirmed by manual chart review. During the study period, 655 cases of KD were identified by International Classification of Diseases codes. Of these, 97 chart-confirmed cases were within risk or control intervals. In analyses, the age-adjusted relative risk for KD following any dose of PCV13 was 0.75 (95% confidence interval, 0.47-1.21). Similarly, the age-adjusted relative risk for KD following any dose of rotavirus vaccine was 0.66 (95% CI, 0.40-1.09). Overall, there was no evidence of an elevated risk of KD following PCV13 or rotavirus vaccines by dose. In addition, no statistically significant temporal clustering of KD cases was identified during days 1 to 70 postvaccination. PCV13 and rotavirus vaccination were not associated with an increased risk of KD in children <2 years of age. Our findings provide additional evidence for the overall safety of PCV13 and rotavirus vaccines.

Implementing a Nurse-Driven Protocol for Pneumococcal Vaccination in an Academic Rheumatology Clinic.

Rheumatology patients are at high risk for complications from pneumococcal infections. The goal of this study was to assess the feasibility of implementing a nurse-driven pneumococcal vaccination protocol based on the 2012 Advisory Committee on Immunization Practices (ACIP) guidelines within an academic rheumatology clinic. Our aims were to increase (1) pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23) monthly vaccination rates in immunosuppressed patients aged 19 to 64 years, and (2) the overall proportion of immunosuppressed patients aged 19 to 64 years who have received both PCV13 and PPSV23 vaccinations by ≥ 10% over a 2-year period. We identified eligible adults in the electronic medical record using a search protocol based on preset medication group. We obtained baseline pneumococcal vaccination rates in 2019, calculating the proportion of patients who were unvaccinated, partially vaccinated (received either PCV13 or PPSV23), or fully vaccinated. We created a pneumococcal vaccination protocol based on 2012 ACIP guidelines and converted it into a standing medical order to be implemented by the nursing staff. Postintervention vaccination rates were calculated monthly and at the end of the study period. Multiple comparison testing was performed to assess for significant postintervention changes. The average rate of monthly vaccination with either PCV13 or PPSV23 increased from 4.3% in 2019 to 12.6% in 2021. The proportion of patients who were fully vaccinated increased from 14.6% in 2019 to 26.2% in 2021. Both changes were statistically significant. It is feasible to employ a nurse-driven protocol for improving pneumococcal vaccination rates in immunosuppressed patients, despite difficulties posed by coronavirus disease 2019 (COVID-19) pandemic disruptions.

Key features of pneumococcal isolates recovered in Central and Northwestern Russia in 2011–2018 determined through whole-genome sequencing

Invasive pneumococcal disease remains one of the leading causes of morbidity and mortality worldwide. In Russia, 13- valent pneumococcal conjugate vaccine (PCV13) was introduced into the childhood immunization programme nationwide in 2014. As part of the Global Pneumococcal Sequencing Project (GPS), we used genome data to characterize 179 pneumococcal isolates collected from Russia in 2011-2018 to investigate the circulating pneumococcal strains using a standardized genomic definition of pneumococcal lineages (global pneumococcal sequence clusters, GPSCs), prevalent serotypes and antimicrobial resistance profiles.We observed high serotype and lineage diversity among the 179 isolates recovered from cerebrospinal fluid (n=77), nasopharyngeal swabs (n=99) and other non-sterile site swabs (n=3). Overall, 60 GPSCs were identified, including 48 clonal complexes (CCs) and 14 singletons, and expressed 42 serotypes (including non-typable). Among PCV13 serotypes, 19F, 6B and 23F were the top three serotypes while 11A, 15B/C and 8 were the top three among non-PCV13 serotypes in the collection. Two lineages (GPSC6 and GPSC47) expressed both PCV13 and non-PCV13 serotypes that caused invasive disease, and were penicillin- and multidrug-resistant (MDR), highlighting their potential to adapt and continue to cause infections under vaccine and antibiotic selective pressure. PCV13 serotypes comprised 92 % (11/12) of the CSF isolates from the children aged below 5 years; however, the prevalence of PCV13 serotype isolates dropped to 53 % (31/58) among the nasopharyngeal isolates. Our analysis showed that 59 % (105/179) of the isolates were predicted to be non-susceptible to at least one class of antibiotics and 26 % (46/179) were MDR. Four MDR lineages (GPSC1, GPSC6, GPSC10 and GPSC47) accounted for 65 % (30/46) of the MDR isolates and expressed PCV13 serotypes (93 %, 28/30).This study provides evidence of high genetic and serotype diversity contributed by a mix of globally spreading and regionally circulating lineages in Russia. The observations suggest that the PCV13 vaccine could be important in reducing both invasive disease and antimicrobial resistance. We also identify potential lineages (GPSC6 and GPSC47) that may evade the vaccine.

Impact of national pneumococcal vaccination program on invasive pneumococcal diseases in South Korea

Following the introduction of pneumococcal conjugate vaccines (PCVs), the rate of invasive pneumococcal disease (IPD) declined, however, IPDs replaced by serotypes that are not included in the vaccine have emerged. We describe the epidemiology of IPD in South Korea over a 4.5-year period, encompassing the impact following introduction of PCV10/13 and PPSV23 into the public immunization program, and assess serotype dynamics in pediatric and adult population. This was a nationwide, retrospective review of surveillance of all IPD cases in Korea between September 2014 to December 2019. We analyzed VT13 (serotypes included in 13-valent conjugate vaccine) and NVT (nonvaccine type) cases by age, sex, IPD type, vaccination status, and deaths. A total of 893 cases with serotype data were included; 306 (34%) VT13 cases and 587 (66%) NVT cases. Serotype 3 (n = 155) was the most common VT13 serotype, followed by serotypes 19A (n = 70) and 14 (n = 28). Among the NVTs, serotype 10A (n = 74) was the most common serotype, followed by serotypes 23A (n = 60) and 34 (n = 58). Persons who had PCV13 vaccination were at lower risk (aOR = 0.11, 95% CI 0.02–0.73, P = 0.022) of death compared to unvaccinated persons. Introduction of PCV10/13 and PPSV23 vaccination program has had different impacts on the serotype-specific IPD across age groups. The most common serotypes included serotypes 3 and 19A (VT13), and 10A, 23A, and 34 (NVT). Our findings suggest continued monitoring in the midst of new vaccine development, and a need to develop novel strategies to mitigate the IPDs from emerging pneumococcal serotypes.

Effect of the of 10-valent pneumococcal conjugate vaccine in Nepal 4 years after introduction: an observational cohort study

In Nepal, Streptococcus pneumoniae (pneumococcus) is a common cause of bacterial pneumonia in children, and is a major health concern. There are few data on the effect of vaccination on the disease or colonisation with pneumococci in the nasopharynx of children in this setting. The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced into the routine infant immunisation schedule in Nepal in 2015. We aimed to investigate the effect of the introduction of PCV10 on pneumococcal carriage and disease in children in Nepal. We did an observational cohort study in children in Nepal. The hospital surveillance study took place in Patan Hospital, Kathmandu, and community studies in healthy children took place in Kathmandu and Okhaldhunga district. For the surveillance study, all children admitted to Patan Hospital between March 20, 2014, and Dec 31, 2019, aged between 2 months and 14 years with clinician-suspected pneumonia, were eligible for enrolment. For the community study, healthy children aged 0-8 weeks, 6-23 months, and 24-59 months were recruited from Kathmandu, and healthy children aged 6-23 months were recruited from Okhaldhunga. We assessed the programmatic effect of PCV10 introduction using surveillance for nasopharyngeal colonisation, pneumonia, and invasive bacterial disease from 1·5 years before vaccine introduction and 4·5 years after vaccine introduction. For the surveillance study, nasopharyngeal swabs, blood cultures, and chest radiographs were obtained from children admitted to Patan Hospital with suspected pneumonia or invasive bacterial disease. For the community study, nasopharyngeal swabs were obtained from healthy children in the urban and rural settings. Pneumonia outcomes were analysed using log-binomial models and adjusted prevalence ratios (aPR) comparing each calendar year after the introduction of the vaccine into the national programme with the pre-vaccine period (2014-15), adjusted for calendar month, age, and sex. Between March 20, 2014, and Dec 31, 2019, we enrolled 2051 children with suspected pneumonia, and 11 354 healthy children (8483 children aged 6-23 months, 761 aged 24-59 months, and 2110 aged 0-8 weeks) to assess nasopharyngeal colonisation. Among clinical pneumonia cases younger than 2 years, vaccine serotype carriage declined 82% (aPR 0·18 [95% CI 0·07-0·50]) by 2019. There was no decrease in vaccine serotype carriage in cases among older unvaccinated age groups. Carriage of the additional serotypes in PCV13 was 2·2 times higher by 2019 (aPR 2·17 [95% CI 1·16-4·05]), due to increases in serotypes 19A and 3. Vaccine serotype carriage in healthy children declined by 75% in those aged 6-23 months (aPR 0·25 [95% CI 0·19-0·33]) but not in those aged 24-59 months (aPR 0·59 [0·29-1·19]). A decrease in overall vaccine serotype carriage of 61% by 2019 (aPR 0·39 [95% CI 0·18-0·85]) was also observed in children younger than 8 weeks who were not yet immunised. Carriage of the additional PCV13 serotypes in children aged 6-23 months increased after PCV10 introduction for serotype 3 and 19A, but not for serotype 6A. The proportion of clinical pneumonia cases with endpoint consolidation on chest radiographs declined from 41% in the pre-vaccine period to 25% by 2018, but rose again in 2019 to 36%. The introduction of the PCV10 vaccine into the routine immunisation programme in Nepal has reduced vaccine serotype carriage in both healthy children and children younger than 2 years with pneumonia. Increases in serotypes 19A and 3 highlight the importance of continued surveillance to monitor the effect of vaccine programmes. This analysis demonstrates a robust approach to assessing vaccine effect in situations in which pneumococcal disease endpoint effectiveness studies are not possible. Gavi, the Vaccine Alliance and the World Health Organization.

Serotype Distribution and Antimicrobial Resistance of Streptococcus pneumoniae Causing Invasive Pneumococcal Disease in Korea Between 2017 and 2019 After Introduction of the 13-Valent Pneumococcal Conjugate Vaccine.

Streptococcus pneumoniae is a serious pathogen causing various infections in humans. We evaluated the serotype distribution and antimicrobial resistance of S. pneumoniae causing invasive pneumococcal disease (IPD) after introduction of pneumococcal conjugate vaccine (PCV)13 in Korea and investigated the epidemiological characteristics of multidrug-resistant (MDR) isolates. S. pneumoniae isolates causing IPD were collected from 16 hospitals in Korea between 2017 and 2019. Serotyping was performed using modified sequential multiplex PCR and the Quellung reaction. Antimicrobial susceptibility tests were performed using the broth microdilution method. Multilocus sequence typing was performed on MDR isolates for epidemiological investigations. Among the 411 S. pneumoniae isolates analyzed, the most prevalent serotype was 3 (12.2%), followed by 10A (9.5%), 34 (7.3%), 19A (6.8%), 23A (6.3%), 22F (6.1%), 35B (5.8%), 11A (5.1%), and others (40.9%). The coverage rates of PCV7, PCV10, PCV13, and pneumococcal polysaccharide vaccine (PPSV)23 were 7.8%, 7.8%, 28.7%, and 59.4%, respectively. Resistance rates to penicillin, ceftriaxone, erythromycin, and levofloxacin were 13.1%, 9.2%, 80.3%, and 4.1%, respectively. MDR isolates accounted for 23.4% of all isolates. Serotypes 23A, 11A, 19A, and 15B accounted for the highest proportions of total isolates at 18.8%, 16.7%, 14.6%, and 8.3%, respectively. Sequence type (ST)166 (43.8%) and ST320 (12.5%) were common among MDR isolates. Non-PCV13 serotypes are increasing among invasive S. pneumoniae strains causing IPD. Differences in antimicrobial resistance were found according to the specific serotype. Continuous monitoring of serotypes and antimicrobial resistance is necessary for the appropriate management of S. pneumoniae infections.

Pneumococcal Conjugate Vaccine Does Not Induce Humoral Response When Administrated Within the Six Months After CD19 CAR T-Cell Therapy

CD19 targeted chimeric antigen receptor-modified T cell therapy (CAR-T) leads to B cell aplasia and low serum immunoglobulin levels. Long-lived CD19–negative plasma cells may persist through the therapy and generate antibodies. There is a paucity of data describing how CAR-T impacts the persistence of antibodies against vaccine-related antigens and the degree to which CAR-T recipients may respond to vaccines. We characterized the effect of CAR-T on pneumococcal immunoglobulin G (IgG) titers and determine whether pneumococcal conjugate vaccine (PCV13) administered after CAR-T develops long-term humoral protection against pneumococcus. A retrospective chart review was performed to identify CAR-T recipients who had serum pneumococcal IgG titers drawn before (baseline) or at days +90, +180, +270, +360, or +540 after CAR-T. We then determined whether they received PCV13 vaccination at these timepoints. IgG concentration ≥1.3 μg/mL was considered protective for that serotype, and patients with ≥6/11 tested vaccine-specific serotypes meeting this threshold were deemed to have humoral protection against pneumococcus. Absolute pneumococcal IgG titers and the proportion of patients with humoral protection, stratified by serotype, and vaccination status were compared by paired nonparametric t-tests. Absolute counts for lymphocyte, CD4 T-cell, and CD19 cell and total IgG level, along with the rate of invasive pneumococcal infections, were measured at these timepoints. A total of 148 CAR-T recipients with pneumococcal IgG titers measured for at least one of the defined time points were identified. At baseline, 25% (19/76) patients with evaluable pneumococcal IgG titers met the definition of humoral protection. Among 44 patients with paired pneumococcal IgG titers at baseline and day+90, absolute IgG titers of all serotypes decreased (geometric mean = 0.41 and 0.32 µg/mL, respectively; P < .001). Thirteen patients were vaccinated following the titer blood draw at day+90 and had paired pneumococcal IgG titers at day+90 and day180. Absolute IgG titers of all vaccine specific serotypes in these vaccinated patients decreased from day+90 to day+180 (geometric mean = 0.36 and 0.29 µg/mL, respectively; P = .03). The proportion of patients meeting the criteria of humoral protection remained the same at day+180 despite vaccination at day+90. The results were similar among 8 patients vaccinated at day+180, as well as 7 patients consecutively vaccinated at day+90 and day+180 with corresponding pneumococcal IgG titers. When all vaccine-specific pneumococcal IgG titers were pooled together by timepoint regardless of vaccination status, the proportion of patients with humoral protection decreased until day+540. Some patients developed humoral protection after vaccination at day+360, maintained seroprotective IgG titers from baseline, or developed protection after receiving intravenous immunoglobulin treatment secondary to recurrent infections. Our study demonstrated that few large B cell lymphoma patients had humoral protection against pneumococcus at baseline, and existing IgG titers decreased after CAR-T. PCV13 vaccination at day+90 or day+180 after CAR-T did not increase humoral protection against pneumococcus. Only at day+540 was there evidence of humoral protection against pneumococcus in a modest proportion of patients. Clinical trials are needed to determine the optimal timing of vaccination, before or after CAR-T, to develop protective immunity against Streptococcus pneumoniae infections.

Global Epidemiology of Vaccine-preventable Bacterial Meningitis.

Global Epidemiology of Vaccine-preventable Bacterial Meningitis.

Polysaccharide and conjugate vaccines to Streptococcus pneumoniae generate distinct humoral responses.

Streptococcus pneumoniae is a major cause of community-acquired pneumonia, bacteremia, and meningitis in older adults worldwide. Two pneumococcal vaccines containing S. pneumoniae capsular polysaccharides are in current use: the polysaccharide vaccine PPSV23 and the glycoconjugate vaccine PCV13. In clinical trials, both vaccines elicit similar opsonophagocytic killing activity. In contrast to polysaccharide vaccines, conjugate vaccines have shown consistent efficacy against nasopharyngeal carriage and noninvasive pneumonia overall and for some prevalent individual serotypes. Given these different clinical profiles, it is crucial to understand the differential immunological responses induced by these two vaccines. Here, we used a high-throughput systems serology approach to profile the biophysical and functional features of serum antibodies induced by PCV13 and PPSV23 at 1 month and 1 year. In comparison with PPSV23, PCV13 induced higher titers across antibody isotypes; more durable antibody responses across immunoglobulin G (IgG), IgA, and IgM isotypes; and increased antigenic breadth. Although titers measured in opsonophagocytic activity (OPA) assays were similar between the two groups, confirming what was observed in clinical studies, serum samples from PCV13 vaccinees could induce additional non-OPA antibody-dependent functions, including monocyte phagocytosis and natural killer cell activation. In a multivariate modeling approach, distinct humoral profiles were demonstrated in each arm. Together, these results demonstrate that the glycoconjugate PCV13 vaccine induces an antigenically broader, more durable, polyfunctional antibody response. These findings may help explain the increased protection against S. pneumoniae colonization and noninvasive pneumonia and the longer duration of protection against invasive pneumococcal disease, mediated by PCV13.

Effect of the Pneumococcal Conjugated Vaccines on Burden of all Cause Pneumonia, Bacterial Pneumonia and Empyema in Children

The aim of this single-center retrospective study was to determine the changes in the burden of allcause pneumonia, bacterial pneumonia and empyema in children aged 0-18 years after the availability of 7-valent pneumococcal conjugated vaccine (PCV7) and 13-valent pneumococcal conjugated vaccine (PCV13) in our country. Children aged 0-18 years who were hospitalized with the diagnosis of pneumonia and treated in Ankara between January 1, 2006 and December 30, 2019 were included in the study. The burden of disease according to the years was calculated as follows: after determining the number of patients with all-cause pneumonia, bacterial pneumonia and the empyema who were admitted to the pediatric infectious diseases service, we divided those numbers to admission numbers to all outpatient clinics in that year as the ratio in 100 000. The years 2006-2007 were accepted as pre-vaccine period, 2009-2010 as PCV7 period and 2012-2019 as PCV13 period. As 2008 and 2011 were the years when PCV7 and PCV13 vaccines implemented into the routine vaccination schedule, they were accepted as transition years and the patient data from these years were not used. All of the patients data were obtained from the patient files. There was a significant decrease in the disease burden of all-cause pneumonia in 0-18 years age and 0-24 months age group after PCV13 period compared to PCV7 period (p<0.001 and p<0.001). A statistically significant decrease was found in all-cause pneumonia among children older than 60 months after PCV13 period compared to PCV7 period and pre-vaccine period (p<0.05 and p<0.01, respectively). When pre-PCV13 (PCV7 and pre-vaccine periods together) and post-PCV13 periods were compared; in 0-18 years age, 0-24 months age and 24-60 months age groups, there was a significant decrease in the burden of disease due to all-cause pneumonia after PCV13 (p<0.001, p<0.001 and p<0.05) period. When the bacterial pneumonia disease burden in PCV13 period was evaluated, bacterial pneumonia disease burden in 0-18 years and 0-24 months age group was found to be significantly lower than in both pre-vaccine and PCV7 periods (p<0.001 and p<0.001). After PCV13 vaccine, the disease burden due to bacterial pneumonia was found to be significantly lower in 0-18 years age, 0-24 months age and older than 60 months age groups compared to pre-PCV13 period (p<0.001, p<0.001 and p<0.01). When PCV7 and PCV13 periods were compared in 0-18 years age group, a significant decrease was found in hospitalizations due to empyema after PCV13 (p<0.05). In conclusion, PCV7 and PCV13 led to a significant reduction in the incidence of all-cause pneumonia and bacterial pneumonia in children.

Aetiology of childhood pneumonia in low- and middle-income countries in the era of vaccination: a systematic review.

BackgroundThis systematic review aimed to describe common aetiologies of severe and non-severe community acquired pneumonia among children aged 1 month to 9 years in low- and middle-income countries.MethodsWe searched the MEDLINE, EMBASE, and PubMed online databases for studies published from January 2010 to August 30, 2020. We included studies on acute community-acquired pneumonia or acute lower respiratory tract infection with ≥1 year of continuous data collection; clear consistent case definition for pneumonia; >1 specimen type (except empyema studies where only pleural fluid was required); testing for >1 pathogen including both viruses and bacteria. Two researchers reviewed the studies independently. Results were presented as a narrative summary. Quality of evidence was assessed with the Quality Assessment Tool for Quantitative Studies. The study was registered on PROSPERO [CRD42020206830].ResultsWe screened 5184 records; 1305 duplicates were removed. The remaining 3879 titles and abstracts were screened. Of these, 557 articles were identified for full-text review, and 55 met the inclusion criteria – 10 case-control studies, three post-mortem studies, 11 surveillance studies, eight cohort studies, five cross-sectional studies, 12 studies with another design and six studies that included patients with pleural effusions or empyema. Studies which described disease by severity showed higher bacterial detection (Streptococcus pneumoniae, Staphylococcus aureus) in severe vs non-severe cases. The most common virus causing severe disease was respiratory syncytial virus (RSV). Pathogens varied by age, with RSV and adenovirus more common in younger children. Influenza and atypical bacteria were more common in children 5-14 years than younger children. Malnourished and HIV-infected children had higher rates of pneumonia due to bacteria or tuberculosis.ConclusionsSeveral viral and bacterial pathogens were identified as important targets for prevention and treatment. Bacterial pathogens remain an important cause of moderate to severe disease, particularly in children with comorbidities despite widespread PCV and Hib vaccination.

Improving Pneumococcal Vaccination Rates in Cochlear Implant Programs: A Systematic Review and Meta-analysis.

To review the literature on pneumococcal vaccination compliance rates among cochlear implant (CI) patients and to examine the utility of intervention programs on increasing vaccination rates. PubMed, Scopus, and CINAHL. A systematic review was performed following PRISMA guidelines. Studies of pneumococcal vaccination rates at baseline and before and after the implementation of a quality improvement (QI) intervention were included. A total of 641 studies were screened, and 13 studies met inclusion criteria. Meta-analyses of pneumococcal vaccination rates pre- and post-QI intervention in CI patients were performed. A total of 12,973 children and adults were included. The baseline PCV13 and PPSV23 vaccination rates were 53.45% (95% CI, 37.02%-69.51%) and 42.53% (95% CI, 31.94%-53.48%), respectively. Comparing children and adults, PCV13 and PPSV23 baseline vaccination rates were not statistically significant. The PPSV23 vaccine rate after QI initiatives was significantly higher than the baseline rate at 83.52% (95% CI, 57.36%-98.46%). After these interventions, patients had a 15.71 (95% CI, 4.32-57.20, P < .001) increased odds of receiving PPSV23 vaccination compared to before QI implementation. The baseline rates of PCV13 and PPSV23 are highly variable and lower than expected, given current vaccination recommendations for CI patients. QI programs appear successful in increasing compliance rates with the PPSV23 vaccination; however, they are still far from full compliance. Further intervention programs with stricter surveillance, monitoring, and follow-up systems are needed to achieve improved compliance with the PCV13 and PPSV23 vaccination in CI recipients.

Genomic features of predominant non-PCV13 serotypes responsible for adult invasive pneumococcal disease in Spain.

Although pneumococcal conjugate vaccines (PCVs) effectively prevent invasive pneumococcal disease (IPD), serotype replacement has occurred. We studied the pangenome, antibiotic resistance mechanisms and presence of mobile elements in predominant non-PCV13 serotypes causing adult IPD after PCV13 vaccine introduction in Spain. We conducted a multicentre study comparing three periods in six Spanish hospitals and analysed through whole genome sequencing representative strains collected in the pre-PCV13, early-PCV13 and late-PCV13 periods. Among 2197 cases of adult IPD identified, 110 pneumococci expressing non-PCV13 capsules were sequenced. Seven predominant serotypes accounted for 42.6% of IPD episodes in the late-PCV13 period: serotypes 8 (14.4%), 12F (7.5%), 9N (5.2%), 11A (4.1%), 22F (3.9%), 24F (3.9%) and 16F (3.6%). All predominant non-PCV13 serotypes were highly clonal, comprising one or two clonal complexes (CC). In general, CC538, CC4048, CC3016F, CC43322F and CC669N, related to predominant non-PCV13 serotypes, were antibiotic susceptible. CC15611A was associated with resistance to co-trimoxazole, penicillin and amoxicillin. CC23024F was non-susceptible to penicillin and resistant to erythromycin, clindamycin, and tetracycline. Six composite transposon structures of the Tn5252-family were found in CC23024F, CC98912F and CC3016F carrying different combinations of erm(B), tet(M), and cat. Pangenome analysis revealed differences in accessory genomes among the different CC, with most variety in CC3016F (23.9%) and more conservation in CC15611A (8.5%). We identified highly clonal predominant serotypes responsible for IPD in adults. The detection of not only conjugative elements carrying resistance determinants but also clones previously associated with vaccine serotypes (CC15611A and CC23024F) highlights the importance of the accessory genome.

Kinetics of pneumococcal antibodies among HIV-exposed, uninfected infants in Botswana

BackgroundStreptococcus pneumoniae is a leading cause of severe infections among children. Despite vaccination, HIV-exposed, uninfected (HEU) children have a higher incidence of invasive pneumococcal disease than HIV-unexposed, uninfected (HUU) children. We sought to compare the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV-13) in HEU and HUU infants. MethodsWe conducted a prospective cohort study of 134 mother-infant dyads in Botswana. Infants received PCV-13 doses at 2, 3, and 4 months through routine clinical care. We measured IgG antibodies specific to vaccine serotypes in sera collected from infants at 0, 5, and 12 months of age. We calculated the proportion of infants with protective IgG levels (≥0.35 µg/mL) to specific pneumococcal serotypes. ResultsAt birth, fewer than half of infants had protective IgG levels to serotypes 1 (38%), 3 (46%), 4 (33%), 5 (23%), 6B (40%), 7F (44%), 9 V (44%), and 23F (46%). Compared to HUU infants (n = 97), HEU infants (n = 37) had lower antibody concentrations at birth to serotypes 5 (p = 0.046) and 19A (p = 0.008) after adjustment for maternal age and infant birth weight. More than 80% of HEU and HUU infants developed protective antibody levels to each of the 13 vaccine serotypes following PCV-13 vaccination. Median concentrations of antibodies to pneumococcal serotypes declined by 55–93% between 5 and 12 months of age, with fewer than half of infants having protective antibody levels to serotypes 1 (47%), 3 (28%), 9 V (44%), 18C (24%), and 23F (49%) at 12 months of age. ConclusionsBoth HEU and HUU infants developed protective antibody responses to PCV-13 administered in a 3 + 0 schedule. However, antibody concentrations to many pneumococcal serotypes waned substantially by 12 months of age, suggesting that a PCV-13 booster dose in the second year of life may be needed to maintain protective pneumococcal antibody levels in older infants and young children.

Burden of pneumococcal disease due to serotypes covered by the 13-valent and new higher-valent pneumococcal conjugate vaccines in the United States

The addition of pneumococcal conjugate vaccines (PCVs) to the United States (US) national immunization program led to significant reductions in incidence, mortality, and associated sequelae caused by pneumococcal disease (PD) in children and adults through direct and indirect protection. However, there remains clinical and economic burden due to PD caused by serotypes not included in the current 13-valent PCV (PCV13) formulation. To address this unmet need, 15-valent PCV (PCV15) and 20-valent PCV (PCV20), containing additional serotypes to PCV13, were recently approved in the US for adults and are anticipated for pediatrics in the near future. The study objective was to estimate the annual number of cases, deaths, and economic burden of PD due to serotypes included in PCV13, PCV15, and PCV20 for both US pediatric and adult populations. An Excel-based model was developed to calculate clinical and economic outcomes using published age-group specific serotype coverage; incidence of invasive PD, community-acquired pneumonia, and acute otitis media; case fatality rates; and disease-related costs. The results showed that across all age groups, the estimated annual PD cases and associated deaths covered by PCV13 serotypes were 914,199 and 4320, respectively. Compared with PCV13 serotypes, the additional 2 and 7 serotypes covered by PCV15 and PCV20 were attributed with 550,475 and 991,220 annual PD cases, as well as 1425 and 3226 annual deaths, respectively. This clinical burden translates into considerable economic costs ranging from $903 to $1,928 million USD that could be potentially addressed by PCV15 and PCV20. The additional serotypes included in PCV20 contribute substantially to the clinical and economic PD burden in the US pediatric and adult populations. Despite the success of the PCV13 pediatric national immunization program and increased adult uptake of PCV13 and 23-valent polysaccharide vaccine, broader PCV serotype coverage is needed across all ages to further reduce pneumococcal disease burden.

The influence of pneumococcal conjugate vaccine-13 on nasal colonisation in a controlled human infection model of pneumococcal carriage in Malawi: a double-blinded randomised controlled trial protocol.

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement, and demonstrate reduced effectiveness against mucosal colonisation. For Malawi, nasopharyngeal carriage of vaccine-type pneumococci is common in vaccinated children despite national roll-out of 13-valent pneumococcal conjugate vaccine (PCV13) since 2011. Our team has safely transferred an established experimental human pneumococcal carriage method from Liverpool School of Tropical Medicine to the Malawi-Liverpool Wellcome Trust Clinical Research Programme, Malawi. This study will determine potential immunological mechanisms for the differential effects of PCV13 on nasal carriage between healthy Malawian and UK populations. We will conduct a double-blinded randomised controlled trial to vaccinate (1:1) participants with either PCV13 or control (normal saline). After a period of one month, participants will be inoculated with S. pneumoniae serotype 6B to experimentally induce nasal carriage using the EHPC method. Subsequently, participants will be invited for a second inoculation after one year to determine longer-term vaccine-induced immunological effects. Primary endpoint: detection of inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: local and systemic innate, humoral and cellular responses to PCV-13 with and without pneumococcal nasal carriage The primary objective of this controlled human infection model study is to determine if PCV-13 vaccination is protective against pneumococcal carriage in healthy adult Malawian volunteers. This study will help us to understand the observed differences in PCV-13 efficacy between populations and inform the design of future vaccines relevant to the Malawian population. Trial Registration: Pan African Clinical Trial Registry (REF: PACTR202008503507113).