Cellular and humoral
responses to fourth SARS-CoV-2 vaccination in a real life cohort of
patients with cancer
To the Editor,
Patients with cancer are at increased risk of adverse outcomes when
infected with SARS-CoV-2 and show an impeded humoral and cellular immune
response to vaccination (1). A fourth vaccination increased the humoral
immunity against SARS-CoV-2 including Omicron sublineages better than
Tixagevimab and Cilgavimab (2). However, data on effects of a fourth
SARS-CoV-2 vaccination on cellular immunity, particularly in relation to
antibody responses, are scarce (3).
Methods : To analyze specific cellular immunity after fourth
immunization, SARS-CoV-2 specific CD4+ /
CD8+ T-cell responses were prospectively measured in 7
patients with histologically confirmed neoplastic disease before and at
the next clinical visit after fourth vaccination against the SARS-CoV-2
spike protein (S) and the receptor binding domain (RBD). Moreover, IgG
against S and RBD of Omicron (BA.4) and Hu-1, respectively were
assessed. A >1.1-fold increase of antigen-specific
proliferated cells and antibody levels compared to baseline was defined
as a vaccine response. Assays were performed as described previously
(4). This study was approved by the Ethics Committee of the Medical
University of Vienna (vote 1427/2022) and performed according to the
Declaration of Helsinki and its amendments. Informed consent was
obtained from all included participants. Descriptive statistical
analysis was performed using GraphPad Prism, Version 9.4.1 (San Diego,
California, USA).
Results : Six patients with solid tumors and one immunocompetent
patient with CNS lymphoma (median age [range] 64 years [45-78],
7 men) were prospectively included and received a fourth vaccination
(one mRNA-1273 and six BNT162b2). Of these patients, 6 patients were
undergoing active anti-neoplastic therapy. The baseline blood sampling
was performed in median 7 months (range 5-9 months) after the third
vaccine dose, while the follow-up blood sampling was done in median 21
days (range: 19-30 days) after the fourth vaccination (Table
1) .
Overall, clear signs of response on either humoral, cellular, or
combined humoral and cellular levels were observed in 6/7 patients.
However, a striking intra- and interpatient heterogeneity of immune
response patterns was evident (Figure 1 ). Only 2/7 patients
(patients 4 and 6) responded with combined increases in S and RBD
specific CD4+ and CD8+ T-cell
proliferation. All other patients showed inconsistent increases in
T-cell activity with low vaccination responses in at least one T-cell
subpopulation. Additionally, humoral response did not consistently
coincide with cellular vaccine responses: patients 4 and 6, who had no
or only a mild (e.g. IgG against S 0.97-fold change and 2.23-fold
change, respectively) increase in antibody levels had a pronounced
cellular vaccine response (e.g. CD4 against S 4-fold change and 134-fold
change, respectively). Interestingly, patient 5 increased antibody
levels against S without corresponding CD4+ responses.
Moreover, patients with distinct antibody increases only showed mediocre
vaccine responses on cellular level (Patients 1, 2 and 7). One patient
(patient 3), showed severely impeded humoral and cellular vaccine
responses to the fourth vaccination applied 433 days after
administration of the last B-cell targeting treatment (Rituximab).
Conclusions : The most important limitation of this prospective
study is its small sample size and the lack of a control group. However,
we observed high intra- and interpatient heterogeneity with clear
indications of humoral, cellular, or combined response to fourth vaccine
in most patients under active treatment. Of note, our observation
indicates long-lasting impairment of specific immune responses after a
fourth vaccine on both humoral and cellular levels as long as 36 months
after last rituximab administration. These findings highlight the need
for reliable identification of and development of management strategies
for SARS-CoV-2 vaccine non-responders among patients receiving
anti-cancer therapies.
References :
1. Mairhofer M, Kausche L, Kaltenbrunner S, Ghanem R, Stegemann M, Klein
K et al. Humoral and cellular immune responses in SARS-CoV-2
mRNA-vaccinated patients with cancer. Cancer Cell.
2021;39 :1171–1172.
2. Mair MJ, Mitterer M, Gattinger P, Berger JM, Valenta R, Fong D et al.
Inhibition of SARS-CoV-2 Omicron BA.1 and BA.4 Variants After Fourth
Vaccination or Tixagevimab and Cilgavimab Administration in Patients
With Cancer. JAMA Oncol Published Online First: September 2022.
doi:10.1001/jamaoncol.2022.4226
3. Debie Y, Van Audenaerde JRM, Vandamme T, Croes L, Teuwen L-A,
Verbruggen L et al. Humoral and Cellular Immune Responses against
SARS-CoV-2 after Third Dose BNT162b2 following Double-Dose Vaccination
with BNT162b2 versus ChAdOx1 in Patients with Cancer. Clin Cancer
Res 2022;:OF1–OF12.
4. Gattinger P, Niespodziana K, Stiasny K, Sahanic S, Tulaeva I,
Borochova K et al. Neutralization of SARS-CoV-2 requires antibodies
against conformational receptor-binding domain epitopes. Allergy2022;77 :230–242.