COBRA-KAI study: COVID-19 vaccination in patients with reduced B-cell and T-cell immunity: response after vaccination of a kaleidoscopic group hematological patients, what*s the impact?

Patients with hematologic conditions have a high mortality risk when infected
with SARS-CoV-2. Protection from infection in this specific patient cohort is
therefore of vast importance. Although vaccination is the strategy of choice to
obtain protection in the general population, it might yield suboptimal
responses in hematologic patients, as many of these patients are
immunocompromised, the extent of which varies considerably. Immunocompromised
states can either be the result of the underlying disease, or can be induced by
therapy. Patients with (malignant) B-cell disorders such as B-cell lymphomas
and leukemias, plasma cell dyscrasias, and patients with acquired functional
asplenia such as sickle cell disease, may have suboptimal humoral immune
responses. It is generally assumed that patients receiving
(immuno-)chemotherapy and/or autologous or allogeneic hematopoietic stem cell
transplantation (HCT) will respond poorly to vaccination. Furthermore, new
upcoming treatments, such as small molecules inhibiting signaling pathways, or
B-cell depleting CD19 CAR-T therapy, not only affect cancer cells but also
impair normal immune function. Robust detailed data on vaccination responses in
these hematological immunocompromised patients are currently lacking.

Assumptions regarding reduced COVID-19 vaccination efficacy has several
consequences. Clinicians may decide to interrupt or defer certain therapies
(e.g. rituximab, lenalidomide) in anticipation of vaccination, which may
negatively impact on prognosis. Second, patients may be advised against
COVID-19 vaccination, possibly wrongfully withholding them protection against
COVID-19. Alternatively, patients may respond less well than anticipated, and
consider themselves protected while in reality they are not. Therefore, data
about vaccination efficacy specific for patients with hematological diseases
are urgently needed.

1.To investigate COVID-19 vaccine responses of the standard schedule of 2
vaccinations with the Moderna mRNA-1273 vaccine (primary schedule) in patients
with hematologic diseases, in particular those patients who are considered
immunocompromised, either due to the hematologic condition, or as a result of
immunosuppressive therapy;
2.To investigate COVID-19 vaccine responses after one or more additional
COVID-19 vaccinations to the primary schedule;
3.To identify those patients that after an initial sufficient response to the
standard vaccination schedule lose this response during follow-up (early
decline of S1-protein antibody titer < 300 BAU/ml after an initial
post-vaccination titer * 300 BAU/ml), and investigate whether these patients
benefit from additional vaccinations.

Observational study

One or more (maximum three) booster vaccinations with the same vaccine in the
same dose as applied in the primary schedule (Moderna), administered to
participants who did not respond, or responded poorly, to the primary schedule.

Burden (see figure 2 in protocol): for the standard vaccination schedule of the
COBRA-KAI (CK) study, blood sampling is scheduled on the days of the first and
of the second vaccination (CK-T0 and CK-T1), with three follow-up blood
sampling visits at one, six and twelve months after the
primary vaccination schedule. Additional COVID-19 vaccinations are as part of
the National Immunisation Program ('Rijksvaccinatieprogramma'). Blood sampling
will be done at the day of each additional vaccination (CK-T3, CK-T5, CK-T7,
CK-T9(?). Response to these additional vaccinations will be measured one month
later.
Blood will be drawn for standard laboratory characteristics, with or without
antibody measurement and 50 ml for biobanking (for in-depth immunologic
analyses). As shown in figure 2 (see protocol), biobanking is scheduled at 11
time-points (CK-TO tot CK-T2 en CK-T4 tot CK-T11).
Blood sampling may cause minor discomfort and the total amount is well below
maximum accepted volumes (64 ml prior to and 4 weeks after each vaccination
(except prior to the additional vaccinations when 14 ml will be collected) and
after 1 year, 11 timepoints equals 704 ml in two years for patients. Patients
will be asked to complete a questionnaire on the eventual diagnosis of COVID-19
infection and its severity following vaccination.
Benefit: Patients will be informed of their response to standard COVID-19
vaccination and 3rd vaccination and they will be counseled about the
interpretation of the results.
Group relatedness: this study will provide information that will be included in
vaccination protocols and guidelines and as such will benefit the patient group
as a whole.