Clinical trial NCT05316831: Immune Response After Pneumococcal Vaccination in Patient With Chronic Lymphocytic Leukemia
Official title: Long Term Effect on Immune Response After Pneumococcal Vaccination in Patients With Chronic Lymphocytic Leukemia and Evaluation of the Effect of Revaccination
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: CLL
Vaccine Response
Lead sponsor: Region Örebro County
Sponsor class: OTHER
First posted: 2022-04-07
Enrollment: 77
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: A randomized, multi-centre trial was conducted between 2013-2016, including 128 patients with untreated CLL from eight hematological clinics in Sweden. Vaccination with polysaccharide pneumococcal vaccine (PPSV23) or conjugated pneumococcal vaccine (PCV13) was performed and the results were published 2018. PCV13 showed a superior immune response, measured as OPA (opsonophagocytic assays) and ELISA (enzyme-linked immunosorbent assay), compared to PPSV23. Immune cells analyses after primary immunization will be performed. Between 2019-2021 a prospective follow up study was conducted of the same cohort and also included a control group. The study participants have been revaccinated with pneumococcal vaccines with the aim to evaluate the effect of repeated dose of PCV13. The antibody response (measured as titer with FMIA (fluorescent multiplexed bead-based immunoassay) and antibody function with MOPA (multiplexed opsonophagocytic assay) will be performed. Studies investigating the dynamics of immune cells before and after primary immunization and revaccination will be performed.

The study will give important answers about the optimal vaccination strategy in patients with CLL and can improve the vaccination recommendations in immunocompromised patients.

Detailed description: Chronic lymphocytic leukemia (CLL) patients have increased risk of pneumococcal infection due to defect T-cells, complements and neutrophil/monocyte function or hypogammaglobulinaemia. Side effects of different treatment modalities add further risk of infection.

Two pneumococcal vaccines are available, non-conjugated pneumococcal polysaccharide vaccines (PPSVs) and protein-conjugated vaccines (PCVs). 23-valent Pneumovax (PPSV23) has been recommended for healthy adults to protect against invasive pneumococcal disease (IPD) in Sweden and other countries for \>30 years. Patients with reduced adaptive immune function respond inadequately to PPSVs. Instead, the 13-valent Prevenar (PCV13) is recommended for a thymus-dependent immunological memory, yielding increased and persistent immune response .

In 2016, Swedish recommendations on pneumococcal vaccination of risk groups were updated, recommending PCV13 plus PPSV23 after \>8 weeks, but only after individual assessment. The evidence in CLL patients is limited but the Swedish CLL-Group has adopted the recommendations. The two vaccines are administrated consecutively to broaden the protection of additional serotype. If previously PPSV23 vaccinated, the PCV13 should be given \>12 months after PSV23 to avoid decreasing antibodies, i.e hyporesponse, but this is not studied in CLL patients.

Between 2013-2016, the investigators conducted a phase III trial at 8 hematological clinics in Sweden, including 126 untreated CLL patients, randomized to PCV13 (n=63) or PPSV23 (n=63) . The immune response was analyzed in terms of antibody induction and functionality, measured by enzyme-linked immunosorbent assay (ELISA) and opsonophagocytosis assay (OPA), respectively. The proportion of responding patients was larger for PCV13 than for PPSV23 after 4 weeks (40% vs. 22%, p=0.03) and 6 months (33% vs. 17%, p=0.04).

This study aims to investigate the persistent antibody protection in CLL patients 4-6 years after vaccination with PCV13 (n=63) vs PPSV23 (n=63), and the effect of revaccination with PCV13 in both groups. Also, the aim is to study if a repeated dose of PCV13 results in improved response, similar to controls after one dose of PCV13, and compared to PCV13 plus PPSV23 revaccination. Secondly, the study investigates the effect of pneumococcal vaccination on incidence of pneumococcal infection and colonization. A control group (N=32) has been included. Peripheral blood mononuclear cell (PBMC) have been collected and further studies on the dynamics of immune cells and cytokines before and after primary immunization and revaccination with polysaccharide vaccines and conjugated vaccines will be investigated.

A sub study was initiated february 2021 in the same cohort for sampling after vaccination against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in the same study cohort, enabling comparison of immune response after administrating mRNA (messenger ribonucleic acid) vaccines.

Eligibility criteria: Inclusion Criteria:

CLL patients earlier included in the Pneumococcal vaccination study 0887x1-20003 (EudraCT No: 2009-012642-22), who have received either PCV13 or PPSV23 are eligible for evaluation

Exclusion Criteria:

1. Patients receiving high dose corticosteroids ( ≥20 mg Prednisolone) or other immunosuppressive drugs that is not part of active CLL treatment (criteria for inclusion after discontinuing high dose corticosteroid treatment, see section 7.3)
2. Patients who have had an allergic reaction to any vaccination in the past
3. Patients with a positive DAT (Direct Antiglobulin Test) or known present or previous hemolysis, ITP (immune thrombocytopenia) and Guillain-Barre
4. Patients failing to give informed consent
5. Patients with ongoing immunoglobulin therapy
6. Patients with known HIV infection
7. Patients who have received a pneumococcal vaccine outside the study protocol within the last 12 months
8. Active febrile infection
9. Increased bleeding risk due to severe thrombocytopenia or other coagulopathies that would, in the opinion of the investigator, contraindicate intramuscular injection (for treatment with oral anticoagulation therapy, see section 7.3) -

Primary outcomes:
measure: Immune response 3-5 years after primary vaccination with a single dose of 13-valent pneumococcal conjugated vaccine (PCV13, Prevenar13®) or conventional 23-valent capsular polysaccharide vaccine (PPSV23, Pneumovax®)
timeFrame: 3-5 years after vaccination
measure: Change in immune response after revaccination.
timeFrame: Before and 8, 16 and 52 weeks after first revaccination
Secondary outcomes:
measure: Prevalence of pneumococcal colonization
timeFrame: Before and 8, 16 and 52 weeks after first revaccination
measure: Effect of pneumococcal revaccination on T- and B-cell subsets
timeFrame: Before, 7 days and 8 weeks after every revaccination. Twelve months after first revaccination
measure: Antibody response after vaccination with PPSV23, PCV13 and mRNA vaccine
timeFrame: Before, 4-8 weeks after every vaccination and 12 months after first pneumococcal revaccination and second mRNA vaccination
measure: Incidence of invasive pneumococcal disease (IPD)
timeFrame: From the initial vaccination to maximum five years after the first dose of revaccination
measure: Effect of pneumococcal revaccination on cytokine levels
timeFrame: Before and 8, 16 and 52 weeks after first revaccination
measure: Immune cell response after vaccination with PPSV23, PCV13 and mRNA vaccine
timeFrame: Before, 4-8 weeks afte0r every vaccination and 12 month after first pneumococcal revaccination and second mRNA vaccination
Other outcomes:
Locations:
city: Örebro
country: Sweden
facility: Magdalena Kättström
Study officials:
affiliation: Universitetssjukhuset Örebro
name: Bertil Uggla, Md, PhD
role: PRINCIPAL_INVESTIGATOR
References: