Patients (pts) with follicular lymphoma (FL) were reported to be at high risk for
hospitalization and death from COVID-19 infection, especially if exposed to anti-CD20
monoclonal antibodies (mAbs)-based therapy. A large amount of studies unequivocally
demonstrated that anti-CD20 mAbs-containing therapies typically impair the development of
protective levels of neutralizing anti-spike antibodies after immunization with full
course of approved mRNA-based COVID-19 vaccines (up to 12 months after last anti-CD20
infusion). Moreover, booster doses seem to induce seroconversion only in a minority of
such pts. On the contrary, preliminary findings seem to suggest that a substantial
proportion of vaccinated pts with B-cell lymphoma (B-NHL) mount detectable
SARS-CoV-2-specific T-cell responses (as measured by assays evaluating IFN-Y secretion
after stimulation with SARS-CoV-2 peptides), independently from humoral response status.

For newly diagnosed FL pts current guidelines suggest to complete the vaccination with
booster dose(s) before treatment initiation, as anti-CD20 mAbs seems to spare
pre-established humoral immunity to COVID-19 vaccine, although data supporting this
finding are scanty.5 Furthermore, data about long term persistence of pre-established
cellular immunity in this setting are lacking, although preliminary findings in
unselected immunosuppressed pts suggest that it decline over time without significant
difference with respect to the general population.

The novel adjuvanted recombinant zoster vaccine demonstrated lower humoral immune
response in pts with B-NHL with respect to other pts, probably due to anti-CD20 therapy,
while cellular immunity was not affected, although the small number of pts requires
further investigation.

Very few data concerning persistence of immunity to childhood vaccines after
anti-CD20-based therapy are available and suggest that humoral immunity to diphtheria and
tetanus may be significantly impaired after therapy.

This is a prospective biological study evaluating the persistence of COVID-19 vaccine and
other vaccines' (zoster, diphtheria and tetanus)-induced immunity in a subgroup of FL
patients undergoing frontline induction immuno-chemotherapy and anti-CD20 maintenance
within the prospective FIL_FOLL19 study (NCT05058404).

After the signature of a specific informed consent, eligible patients will receive a
questionnaire evaluating vaccination history, past infection history and treatment, and
passive immune prophylaxis (e.g. tixagevimab/cilgavimab administration). A baseline blood
sample will be collected before the initiation of treatment and will be sent to the
central laboratory, where specific analyses evaluating vaccine-induced cellular and/or
humoral immunity against COVID-19, VZV, diphtheria and tetanus will be performed.

COVID-19 cellular and humoral immunity will be evaluated in all patients at all available
timepoints.

Humoral and cellular immunity for VZV will be evaluated for all patients at study entry.
In the subgroup of patients with a detectable serologic response at study entry, humoral
and cellular immunity will be also evaluated at all available later timepoints.

Humoral immunity for diphtheria and tetanus will be evaluated for all patients at study
entry. In the subgroup of patients with a detectable serologic response at study entry,
humoral immunity will be also evaluated at all available later timepoints.

T-cell immunological parameters will be evaluated at study entry and 12 months after EOI
(or early withdrawal).