Chronic lymphocytic leukemia (CLL) is the most common malignant blood disorder in the western world. It is characterized by an accumulation of malignant, mature-appearing but functionally incompetent B-lymphocytes in blood, bone marrow and lymphoid tissues. Patients with CLL are susceptible to infections, this arising from humoral and cell-mediated immunodeficiency associated with CLL itself as well as from treatment of the malignancy. Infections are the most frequent cause of death in these patients. They are especially prone to infections in the respiratory tract, for example pneumonias and sinusitis. Streptococcus pneumoniae is the most prominent single pathogen. In advanced stages of the disease opportunistic pathogens such as herpes viruses and fungi also become more prevalent. Treatment of CLL does not improve humoral immunity, and many new effective treatments - for example monoclonal antibodies - also disturb cell-mediated immunity. Prophylactic antimicrobials or intravenous immunoglobulins have not solved the problem of infections. Active immunization by vaccines has effectively eradicated many infections among the healthy population, but their impact in CLL patients has remained unclear. The vaccines mostly used are bacterial polysaccharides, which are, however, weak immunogens, especially when the immune system is compromised. Conjugation of polysaccharides to protein carrier renders them more immunogenic, and they act like T-cell-dependent antigens and also induce an immunological memory.
In this series we evaluated the specific antibody responses to different types of vaccine antigens in CLL patients, and sought factors predictive of vaccination-induced antibody responses. Special interest focused on conjugate vaccines, and Streptococcus pneumoniae, which is the main pathogen underlying serious infection in patients with CLL.
The study cohorts comprised CLL patients from Tampere and Turku University Hospitals. The majority had early-stage disease without a heavy treatment history. The control groups consisted of immunologically healthy persons. The polysaccharide vaccine used in the studies was 23-valent pneumococcal vaccine (Pnu-Immune®), the protein vaccine tetanus toxoid (Tetanus-d-rokote®). The conjugate vaccines were Haemophilus influenzae type b (HibTITER®) and 7-valent pneumococcal conjugate vaccine (Prevenar®). We measured concentrations of specific serum antibodies to vaccine antigens before and one month after vaccination.
Vaccination responses to plain polysaccharide pneumococcal antigens were very weak in CLL patients compared to controls, only a few in fact evincing any response at all. In turn, both Haemophilus influenzae type b (Hib) and 7-valent pneumococcal conjugate vaccines were more immunogenic in CLL patients. A high proportion of patients reached the concentrations considered protective after vaccination with conjugate vaccines. The response rates were compromised by advanced disease state, chemotherapy and hypogammaglobulinemia. Every fourth CLL patient mounted a significant response to at least 6 pneumococcal antigens after 7-valent pneumococcal conjugate vaccine. Almost 40% of them developed a significant response to at least six pneumococcal antigens out of the seven included in the vaccine if the vaccine had been administered at an early stage in the disease. Similar rates were reached with Hib conjugate vaccine, where one in five CLL patients developed a significant response.
Pneumococcal polysaccharide vaccine did not significantly increase antibody concentrations in CLL patients after vaccination. Pneumococcal and Hib conjugate vaccines, in turn, proved considerably more immunogenic. Conjugate vaccines appeared to be more effective in younger CLL patients with normal serum immunoglobulin concentrations and less advanced stage of disease. In any case, even many patients with advanced CLL disease and poor prognostic factors such as unmutated CLL responded to both conjugate vaccines. According to the present findings it seems reasonable to vaccinate all CLL patients with conjugate vaccines, and the vaccination should be delivered early in the course of the disease.
