Pneumococcal vaccination in inflammatory rheumatic disease and in splenectomy patients. From antibody response to memory cells

Abstract: Objectives:The overall aim of the dissertation is to examine antibody response to immunization with pneumococcal vaccine in patients with inflammatory rheumatic disease (IRD), in relation to disease-modifying antirheumatic drug (DMARD) treatments, and in postsplenectomy patients.Methods:(I) Splenectomized patients without previous pneumococcal conjugate vaccine (PCV) immunization were invited to receive one dose 13-valent PCV (PCV13). Blood was drawn before and 4-6 weeks after PCV13. Serotype-specific antibody responses were determined using a multiplex fluorescent microsphere immunoassay (MFMI). (II and III) Consecutive patients with systemic vasulitis, rheumatoid arthritis (RA), and primary Sjögren’s syndrome (pSS), and healthy controls (HC) were invited to receive immunization with one dose PCV13. Serotype 6B and 23F IgG were determined before and 4-6 weeks after PCV13 using enzyme-linked immunosorbent assay (ELISA) and functionality of antibodies (23F) with an opsonophagocytic activity (OPA) assay. Positive antibody response (AR) was defined as ≥2-fold rise in pre- to postvaccination IgG. (IV) Patients with RA or systemic vasculitis and HC were invited to receive PCV and a booster dose with 23-valent pneumococcal polysaccharride vaccine (PCV23) after at least 8 weeks. IgG was determined before PCV and PPV23 and 4-6 weeks after using MFMI and OPA assay. (V) RA patients planned to start methotrexate (MTX) treatment, patients without DMARD and HC were included. Blood was obtained at inclusion, at immunization with PCV13 (after at least 6 weeks on MTX) and 7 days after for flow cytometric phenotyping of lymphocytes, and 4-6 weeks after for MFMI.Results:Splenectomy patients (n=24) with previous PPV23, received a dose of PCV13, and geometric mean concentration (GMC) increased for 9/12 serotypes. Patients with systemic vasculitis (n=49) and ongoing standard of care therapy received one dose of PCV13, IgG GMC for serotypes 6B and 23F increased, and there was no significant difference in antibody response (≥2-fold rise in IgG) compared to HC. Although OPA increased after PCV13, it was lower in patients compared to HC (p=0.001). In patients with RA (n=50) and pSS (n=15) without ongoing DMARD treatment IgG GMC for 6B and 23F and OPA increased, and the proportions with positive antibody responses for RA (52%) were similar to HC (55%, n=49). Patients with IRD treated with rituximab (RTX, n=30), abatacept (n=23), conventional DMARD (cDMARD, n=27) and HC (n=28) received immunization with PCV+PPV23. Antibody response improved after PPV23 in cDMARD (both 2-fold AR and OPA), and ABT (2-fold AR but not OPA), but no improvement was seen in RTX treated patients. Start of MTX treatment in RA patients resulted in decreased Th17 cells, and impaired memory B cell and plasmablast responses after PCV13.Conclusions:PCV is immunogenic as a booster dose in splenectomized patients with previous PPV23 immunization. PCV is immunogenic in systemic vaculitis patients with ongoing standard of care treatment, although functionality is lower compared to HC. Antibody response is not impaired in RA and pSS patients without DMARD treatment compared to HC. A PPV23 booster could be recommended in IRD patients with cDMARD, and ABT, but vaccination needs to be completed before starting RTX. MTX treatment can have negative effects on memory B cells following PCV13.