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Methotrexate reduces circulating Th17 cells and impairs plasmablast and memory B cell expansions following pneumococcal conjugate immunization in RA patients.

ABSTRACT: Methotrexate (MTX) impairs antibody response after pneumococcal vaccination. We aimed to investigate differences in phenotypes of circulating B and T cells after pneumococcal conjugate vaccine (PCV) in rheumatoid arthritis (RA) patients on MTX (MTX group), RA without disease-modifying drugs (0DMARD), and controls (HC). MTX group (n = 11), 0DMARD (n = 12) and HC (n = 13) were studied. Blood samples were collected: before MTX, ≥ 4 weeks on stable MTX dose (prevaccination), and 7 days postvaccination (MTX group), and pre- and 7 days postvaccination (0DMARD and HC). Phenotypes of B- and T cell subsets were determined using flow cytometry. Serotype-specific IgG were quantified using multiplex bead assay, pre- and 4-6 weeks postvaccination. Concentrations of plasmablasts and switched memory B cells increased after PCV in HC (both p = 0.03) and the 0DMARD group (p = 0.01 and p = 0.02), but not in the MTX group. Postimmunization plasmablasts were lower in MTX group, compared to the 0DMARD group and HC (p = 0.002 and p < 0.001). Th17 cells decreased after MTX start (p = 0.02), and increased in HC after immunization (p = 0.01). Postimmunization plasmablasts correlated with mean antibody response ratio in all RA patients (R = 0.57, p = 0.035). Methotrexate reduced Th17 cells and blocked activation of plasmablasts and switched memory B cells following polysaccharide-protein conjugate antigen challenge in RA.

SUBMITTER: Nived P

PROVIDER: S-EPMC8080705 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Streptococcus pneumoniae is a major human pathogen responsible for over 317000 deaths in children <5 years of age with the burden of the disease being highest in low- and middle-income countries including South Africa. Following the introduction of the 7-valent and 13-valent pneumococcal conjugate vaccine (PCV) in South Africa in 2009 and 2011, respectively, a decrease in both invasive pneumococcal infections and asymptomatic carriage of vaccine-type pneumococci were reported. In this study, we described the changing epidemiology of the pneumococcal carriage population in South Africa, by sequencing the genomes of 1825 isolates collected between 2009 and 2013. Using these genomic data, we reported the changes in serotypes, Global Pneumococcal Sequence Clusters (GPSCs), and antibiotic resistance before and after the introduction of PCV13. The pneumococcal carriage population in South Africa has a high level of diversity, comprising of 126 GPSCs and 49 serotypes. Of the ten most prevalent GPSCs detected, six were predominantly found in Africa (GPSC22, GPSC21, GPSC17, GPSC33, GPSC34 and GPSC52). We found a significant decrease in PCV7 serotypes (19F, 6B, 23F and 14) and an increase in non-vaccine serotypes (NVT) (16F, 34, 35B and 11A) among children <2 years of age. The increase in NVTs was driven by pneumococcal lineages GPSC33, GPSC34, GPSC5 and GPSC22. Overall, a decrease in antibiotic resistance for 11 antimicrobials was detected in the PCV13 era. Further, we reported a higher resistance prevalence among vaccine types (VTs), as compared to NVTs; however, an increase in penicillin resistance among NVT was observed between the PCV7 and PCV13 eras. The carriage isolates from South Africa predominantly belonged to pneumococcal lineages, which are endemic to Africa. While the introduction of PCV resulted in an overall reduction of resistance in pneumococcal carriage isolates, an increase in penicillin resistance among NVTs was detected in children aged between 3 and 5 years, driven by the expansion of penicillin-resistant clones associated with NVTs in the PCV13 era.

Project description:IntroductionAlthough the pneumococcal conjugate vaccine (PCV) has been introduced into select state immunization programs (SIPs) in India, many children remain unvaccinated. Recently, India's Advisory Committee on Vaccines & Immunization Practices recommended PCV on the pediatric immunization schedule nationally. This study estimates the public health and economic impact of introducing either Pfizer's 13-valent PCV (PCV13-PFE), GlaxoSmithKline's 10-valent PCV (PCV10-GSK), or Serum Institute of India's 10-valent PCV (PCV10-SII) into every pediatric SIP.MethodsA model was developed to predict the disease cases, deaths, and costs associated with implementing PCV13-PFE, PCV10-GSK, or PCV10-SII in SIPs compared to no vaccination program across a 5-year period (2021-2025). State and national-level uptake rate and clinical and economic input parameters were collected from published literature. Disease outcomes included invasive pneumococcal disease, inpatient and outpatient pneumonia, and otitis media. Costs were estimated as vaccine-related costs and direct medical costs incurred to the healthcare system. Results were reported by individual state and aggregated nationally.ResultsEstimated over 5 years, implementing PCV13-PFE in SIPs could avert 12.1 million cases and save 626,512 lives among children under 5 years old compared to no vaccination. This corresponds to net national cost savings of over $1.0 billion. Both lower-valent PCVs are estimated to provide less economic savings than PCV13-PFE inclusive of vaccine-related costs. Compared with PCV13-PFE, implementing PCV10-GSK or PCV10-SII nationally is estimated to have a smaller public health impact, with PCV10-GSK averting 8.4 million cases (436,577 deaths) and PCV10-SII preventing 10.3 million cases (531,545 deaths) in India compared to no vaccination, respectively.ConclusionImplementation of PCV13-PFE throughout India is estimated to provide greater public health and economic benefits than PCV10-GSK or PCV10-SII SIPs. Our analysis highlights the substantial disease cases, deaths, and health system cost savings that may be realized from implementing PCV programs throughout India.

Project description:IntroductionThe aim of present study is to inverstigate the association between antibody levels after vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) and subsequent serious pneumococcal infections in rheumatoid arthritis (RA) and spondylarthropathy (SpA) patients.MethodsA cohort of 497 patients (RA=248 and SpA=249) received a single dose of PCV7. At vaccination, patients were treated with methotrexate (MTX; n=85), anti-tumour necrosis factor (anti-TNF) + MTX (n=169), anti-TNF monotherapy (n=158) and non-steroidal anti-inflammatory drugs (NSAIDs)/analgesics (n=85). Antibody levels of serotypes 6B and 23B were analyzed before and 4 to 6 weeks after vaccination using standard enzyme-linked immunosorbent assay (ELISA). Serious pneumococcal infections (pneumonia/lower respiratory tract infection, meningitis, sepsis, septic arthritis) occurring within 4.5 years after vaccination were identified in the Skåne Healthcare Register using the International Classification of Diseases, tenth revision (ICD-10) codes. The association between post-vaccination antibody levels and protection against infections and determination of protective cutoff levels was explored using receiver operating characteristic (ROC) curves. Predictors of infection were studied using regression analyses.ResultsEighteen infections were registered in 15 patients before vaccination and 27 infections in 23 patients after vaccination. Patients with serious infections after vaccination had significantly lower post-vaccination antibody titres for both 6B (P=0.04) and 23 F (P=0.04). Post-vaccination antibody levels of at least 1.29 mg/L and 1.01 mg/L for 6B and 23, respectively, were associated with better protection from serious infections. Higher age, concomitant prednisolone but not MTX or anti-TNF were associated with such infections.ConclusionsPatients with more robust antibody responses after vaccination with pneumococcal conjugate vaccine were less likely to suffer from serious infections. High age and prednisolone at vaccination were associated with putative serious pneumococcal infections in this cohort.Trial registration numberEudraCT EU 2007-006539-29 and NCT00828997 . Registered 23 January 2009.

Project description:BackgroundThe burden of pneumococcal disease in China is high, and a 13-valent pneumococcal conjugate vaccine (PCV13) recently received regulatory approval and is available to Chinese infants. PCV13 protects against the most prevalent serotypes causing invasive pneumococcal disease (IPD) in China, but will not provide full societal benefits until made broadly available through a national immunization program (NIP).ObjectiveTo estimate clinical and economic benefits of introducing PCV13 into a NIP in China using local cost estimates and accounting for variability in vaccine uptake and indirect (herd protection) effects.MethodsWe developed a population model to estimate the effect of PCV13 introduction in China. Modeled health states included meningitis, bacteremia, pneumonia (PNE), acute otitis media, death and sequelae, and no disease. Direct healthcare costs and disease incidence data for IPD and PNE were derived from the China Health Insurance and Research Association database; all other parameters were derived from published literature. We estimated total disease cases and associated costs, quality-adjusted life years (QALYs), and deaths for three scenarios from a Chinese Payer Perspective: (1) direct effects only, (2) direct+indirect effects for IPD only, and (3) direct+indirect effects for IPD and inpatient PNE.ResultsScenario (1) resulted in 370.3 thousand QALYs gained and 12.8 thousand deaths avoided versus no vaccination. In scenarios (2) and (3), the PCV13 NIP gained 383.2 thousand and 3,580 thousand QALYs, and avoided 13.1 thousand and 147.5 thousand deaths versus no vaccination, respectively. In all three scenarios, the vaccination cost was offset by cost reductions from prevented disease yielding net costs of ¥29,362.32 million, ¥29,334.29 million, and ¥13,524.72 million, respectively. All resulting incremental cost-effectiveness ratios fell below a 2x China GDP cost-effectiveness threshold across a range of potential vaccine prices.DiscussionInitiation of a PCV13 NIP in China incurs large upfront costs but is good value for money, and is likely to prevent substantial cases of disease among children and non-vaccinated individuals.

Project description:BackgroundInvasive pneumococcal disease declined among children and adults after the introduction of the pediatric heptavalent pneumococcal conjugate vaccine (PCV7) in 2000, but its effect on pneumococcal meningitis is unclear.MethodsWe examined trends in pneumococcal meningitis from 1998 through 2005 using active, population-based surveillance data from eight sites in the United States. Isolates were grouped into PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F), PCV7-related serotypes (6A, 9A, 9L, 9N, 18A, 18B, 18F, 19B, 19C, 23A, and 23B), and non-PCV7 serotypes (all others). Changes in the incidence of pneumococcal meningitis were assessed against baseline values from 1998-1999.ResultsWe identified 1379 cases of pneumococcal meningitis. The incidence declined from 1.13 cases to 0.79 case per 100,000 persons between 1998-1999 and 2004-2005 (a 30.1% decline, P<0.001). Among persons younger than 2 years of age and those 65 years of age or older, the incidence decreased during the study period by 64.0% and 54.0%, respectively (P<0.001 for both groups). Rates of PCV7-serotype meningitis declined from 0.66 case to 0.18 case (a 73.3% decline, P<0.001) among patients of all ages. Although rates of PCV7-related-serotype disease decreased by 32.1% (P=0.08), rates of non-PCV7-serotype disease increased from 0.32 to 0.51 (an increase of 60.5%, P<0.001). The percentages of cases from non-PCV7 serotypes 19A, 22F, and 35B each increased significantly during the study period. On average, 27.8% of isolates were nonsusceptible to penicillin, but fewer isolates were nonsusceptible to chloramphenicol (5.7%), meropenem (16.6%), and cefotaxime (11.8%). The proportion of penicillin-nonsusceptible isolates decreased between 1998 and 2003 (from 32.0% to 19.4%, P=0.01) but increased between 2003 and 2005 (from 19.4% to 30.1%, P=0.03).ConclusionsRates of pneumococcal meningitis have decreased among children and adults since PCV7 was introduced. Although the overall effect of the vaccine remains substantial, a recent increase in meningitis caused by non-PCV7 serotypes, including strains nonsusceptible to antibiotics, is a concern.

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Methotrexate reduces circulating Th17 cells and impairs plasmablast and memory B cell expansions following pneumococcal conjugate immunization in RA patients.

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