Response Is Seen to Conjugate Vaccine but Not to Polysaccharide Vaccine Twelve Months After Rituximab.

After therapy with the monoclonal antibody anti-CD20 rituximab ® (R), normal B-cells are depleted and their recovery in blood is delayed until six-twelve months in patients with relapsed low-grade lymphoma treated with four infusions of R. In patients treated with R-chemotherapy or high-dose therapy after R-purged autologous graft, the B-cell recovery is postponed further. The efficacy of active immunization against various bacterial and viral infections of R- treated patients has been debated as total level of immunoglobulin (Ig) M has been shown to decrease during prolonged treatment with R and humoral T cell-independent response might be defect due to lack of B-cells.

To evaluate antibody-response to two vaccines after two timepoints of vaccination.

An open randomized study of patients with B-cells lymphoma vaccinated six or twelve month after last treatment with R (Mabthera® Hoffman-LaRoche, Basel, Switzerland) with or without chemotherapy. Pneumococcal polysaccharide vaccine, Pneumo23® (Sanofi Pasteur MSD), assessed T-cell–independent antibody response and conjugated H. influenza type b-vaccine, Act-Hib® (Sanofi Pasteur MSD), evaluated combined B-cell/T-cell pathway. The patients randomized to vaccination at six months and without response, were revaccinated after further six months. Blood samples were collected immediately before vaccination and four weeks after. Serum was separated, frozen to −20 degrees C, sent to the Division of Microbiology, Statens Seruminstitut, Copenhagen, Denmark for analyses. A modified enzyme-linked assay for measuring type-specific anti-pneumococcal capsular polysaccharide antibodies for 6 pneumococcal serotypes (1, 4, 7F, 14, 18C, 19F) was used and a geometrical mean value for the total titer of antibody was calculated. The definition of protective response was determined to >39 arbitrary units/ml. Total Ig antibodies to the capsular polysaccharide of Haemophilus influenzae type b (HbPs) was measured by ELISA. An anti-HbPs antibody titer of >1 μg/ml was recorded as a protective response after immunization. Blood samples for flow cytometry analysis, including CD19+ and CD20+ B-cell counts, were drawn at the time of vaccination and four weeks after.

Nine patients, age 56–73 years, six females and three males, were randomized to vaccination; four at six months and five at twelve months after last rituximab treatment. Five patients with follicular lymphoma (FL) grade 2 and one with marginalzone lymphoma (MZL) had received single R, one of these in combination with alfa-interferon in a clinical phase II trial. One patient with mantle cell lymphoma (MCL) and one with follicular centroblastic lymphoma were treated with R-CHOP-21 × 8 prior to vaccination. One female patient with MZL randomized to vaccination at twelve months, dropped out because of progression of disease. Vaccination with Pneumo23® resulted in a protective response of pneumococcal antibodies in only one out of eight (12,5 %) patients. This responding patient had MZL treated with R 375 mg weekly x4 during 2 courses, and was randomized to vaccination 6 months after last R and also showed a response to Act-Hib vaccine. Further four patients had an immunization response to act Hib vaccine, one with FL randomized to vaccination six months after R and three after twelve months, two with FL and one with MCL. One patient was revaccinated after twelve months and had no response neither with Pneumo23® or Act-Hib® vaccine. The percentage CD19+ and CD20 + B-cells in the lymphocyte gate (by flow cytometry) was low in all patients at the time of vaccination and four weeks after, but showed a slight increase with time (0,04, 0,26, 0,42, 0,54 % and 0,24, 0,6, 0,6, 1,26, 1,0 % at six and twelve months after R, respectively).

Conjugate vaccine is more potent to give immune response than polysaccharide vaccine after R-therapy in patients with B cell lymphoma. Despite deficient recovery of B-cells cells, five of eight (62,5 %) patients responded to the conjugate vaccine Act-Hib®. The longstanding effect on the immune system of antibody therapy has to be further studied.

No relevant conflicts of interest to declare.