The optimal interval before receiving SARS-COV-2 vaccination for patients who have received Anti-CD 20 monoclonal antibodies

Figures & data

Figure 1. Flow chart describing the study search and selection process.

Table 1. List of the included studies.

Author	Time since the final anti-CD20 therapy	Vaccine	No. of humoral analysis	% responders	B cell counts	Population(disease)
Avivi et al [8]		BP	42	31.0	4.8/ul	DLBCL,B-NHL(FL,MZL,MCL)
	≤6 months		19	10.5
	>6 months		23	47.8
Bitoun et al [9]	≤6 months	BP	24	29.2	NA	AID
Bonelli et al [10]	6 months	BP,M,mRNA,CV	55	27.3	NA	Arthritis,Connective tissue diseases,Vasulitis,MS,IgG4-related disease
Brill et al [11]		BP	27	51.9	NA	MS
	<5 months		17	35.5
	≥5 months		9	88.9
Buchwinkler et al [12]	8 months	BP,mRNA	30	46.7	NA	CKD
Carruthers et al [13]	≤12 months	AZ,BP	15	77.8	NA	AAV
Cohen et al [14]	3 months	BP	34	8.8	NA	VAHL(lymphoma,myeloma)
Diefenbach et al [15]	42d	BP, M	24	25	NA	NHL,CLL,SLL,DLBCL,FL,MCL,MZL,Low-grade B cell lymphoma,BL
Firinu et al [16]	5.5 months	BP	7	28.6	NA	IMIDs(RA,SLE,MSD)
Gadani et al [17]	30d	JJ,M,BP,unsure	39	56.4	NA	MS
Gurion et al [18]	0-45d	BP	34	2.9	NA	Lymphomas
	46-120d		21	23.8
	121-180d		4	25
	181-365d		7	12.3
	>366d		21	81.0
Haidar et al [19]	≤12 months	BP,M,mRNA,CV,JJ	51	17.7	NA	IDD
Herishanu et al [4]	5 months	BP	22	50	NA	CLL
	>12 months		55	94.1
Jinich et al [20]		BP.M	56	51.8	>5ul	RA,SLE,Sjögren’s syndrome,SSc,PMR,IgG4-related disease,ANCA-associated vasculitis
				48.2	0/ul
	<6 months		21	14.9
	6~12 months		11	45.5
	>12 months		24	87.5
König et al [21]	4 months	BP	183	20.2	NA	MS
Kornek et al [22]	6 months	BP,M	82	33	NA	MS
Kornek et al [23]	6 months	M	82	69.5	NA	MS
Krasselt et al [24]	215d	JJ,M,BP,AZ	29	10.3	0/ul	autoimmune inflammatory rheumatic diseases
Lim et al [25]	6 months	BP, CV	31	45.2	1/ul	HL
	7–12 months		4	75
	>12 months			100
Madelon et al [6]	24.9 weeks	BP, M	26	3.8	0/ul	MS, RD
Marty et al [26]		BP,M,JJ	19	94.7		AVV
			11	90.9	<1/ul
			8	100.0	≥1/ul
Moor et al [27]	≤6 months	BP, M	96	49.0	NA	autoimmune disease, malignant tumour, renal transplantation
	6~12 months		96	67.7
Novak et al [28]	15.1 weeks	BP	60	13.5	NA	MS
Perry et al [29]	>6 months	BP	66	66.7	NA	B-NHL
	≤6 months		55	7.3
	>9 months		51	84.3
	≤9 months		70	7.1
Schulz et al [30]	166 days	M	120	67	NA	Hematological malignances
Stefanski et al [31]	9 months	BP,M,CV	19	42.1	10.0/ul	RA, AVV
Tanguay et al [32]		BP, M	55	45.5	0~5/ul	DLBCL,B-NHL(FL,MZL,MCL,LPL,CLL)
	≤1 year		22	4.5
	1~2 years		16	56.3
	>2 years		17	88.2
Tvito et al [33]	<6 months	BP	28	3.6	NA	NHL

AAV, antineutrophil cytoplasmic antibody; AID, autoimmune diseases; AZ, Astra-Zeneca; B-NHL, B-cell non-Hodgkin lymphoma; BL, Burkitt lymphoma; BP, BioNTech-Pfizer; CLL Chronic Lymphocytic leukaemia; DLBCL, diffuse large cell B-cell lymphoma; CV, CoronaVac; FL, follicular lymphoma; HL, Hodgkin lymphoma; LBCL, Low-grade B cell lymphoma; IDD, immune deficiency disorders; IMIDs, immune-mediated inflammatory diseases; JJ, Johnson-Johnson; M, Moderna; MCL, mantle cell lymphoma; MS, Multiple Sclerosis; MSD, miscellaneous systemic disorders; MZL, marginal zone lymphoma; NHL, Non-Hodgkin lymphoma; RA, rheumatoid arthritis, SLE, systemic lupus erythematosus; VAHL, hypermetabolic lymphadenopathy.

Figure 2. Humoral immune responses across all included studies.

Figure 3. Humoral immune responses according to prespecified subgroups of 3-6, 6, 6–9 and 9–12 months since the last dose of anti- CD20 therapy.

Figure 4. ROC curve on the time interval of SARS-CoV-2 vaccination in 1455 patients treated with anti-CD20.The vertical coordinates indicate that all patients who actually received the vaccine were greater than 5.5 months from the last dose of anti-CD20 monoclonal antibody therapy were not infected with the COVID-19. The abscissa indicates that all patients who actually received the vaccine were more than 5.5 months from the last dose of anti-CD20 monoclonal antibody therapy were infected with the COVID-19.

Figure 5. Funnel plot of all included studies.

Avivi I, Luttwak E, Saiag E, et al. Bnt162b2 mRNA COVID-19 vaccine booster induces seroconversion in patients with B-cell non-Hodgkin lymphoma who failed to respond to two prior vaccine doses. Br J Haematol. 2022;196(6):1329–1333. DOI:10.1111/bjh.18029

 PubMed Web of Science ®Google Scholar

Bitoun S, Henry J, Desjardins D, et al. Rituximab impairs b cell response but not t cell response to COVID-19 vaccine in autoimmune diseases. Arthritis Rheumatol. 2021;74(6):927–933. DOI:10.1002/art.42058

 Web of Science ®Google Scholar

Bonelli M, Mrak D, Tobudic S, et al. Additional heterologous versus homologous booster vaccination in immunosuppressed patients without SARS-CoV-2 antibody seroconversion after primary mRNA vaccination: a randomised controlled trial. Ann Rheum Dis. 2022;81(5):687–694. DOI:10.1136/annrheumdis-2021-221558

 PubMed Web of Science ®Google Scholar

Brill L, Raposo C., Rechtman A. et al. SARS-CoV-2 third vaccine immune response in MS patients treated with ocrelizumab. medRxiv. 2022;2022.01.26.22269876. https://doi.org/10.1101/2022.01.26.22269876

 Google Scholar

Buchwinkler L, Solagna CA, Messner J, et al. Antibody response to mRNA vaccines against SARS-CoV-2 with chronic kidney disease, hemodialysis, and after kidney transplantation. J Clin Med. 2022;11(1):148. DOI:10.3390/jcm11010148

 Web of Science ®Google Scholar

Carruthers JE, Wells J, Gupta A, et al. Response to vaccination against sars-COV-2 in patients with antineutrophil cytoplasmic antibody-associated vasculitis with renal involvement. Front Med (Lausanne). 2022;8. DOI:10.3389/fmed.2021.817845.

 PubMed Web of Science ®Google Scholar

Cohen D, Hazut Krauthammer S, Cohen YC, et al. Correlation between BNT162b2 mRNA Covid-19 vaccine-associated hypermetabolic lymphadenopathy and humoral immunity in patients with hematologic malignancy. Eur J Nucl Med Mol Imaging. 2021;48(11):3540–3549. DOI:10.1007/s00259-021-05389-x

 PubMed Web of Science ®Google Scholar

Diefenbach C, Caro J., Koide A. et al. Impaired humoral immunity to sars-cov-2 vaccination in non-Hodgkin lymphoma and cll patients. medRxiv. 2021;2021.06.02.21257804. https://doi.org/10.1101/2021.06.02.21257804

 Google Scholar

Firinu D, Perra A., Campagna M. et al. Evaluation of antibody response to BNT162b2 mRNA COVID-19 vaccine in patients affected by immune-mediated inflammatory diseases up to 5 months after vaccination. Clin Exp Med. 2022;22: 477–485. https://doi.org/10.1007/s10238-021-00771-3

 PubMed Web of Science ®Google Scholar

Gadani SP, Reyes-Mantilla M., Jank L. et al. Discordant humoral and T cell immune responses to SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy. medRxiv. 2021;2021.08.23.21262472. https://doi.org/10.1101/2021.08.23.21262472

 Google Scholar

Gurion R, Rozovski U, Itchaki G, et al. Humoral serologic response to the BNT162b2 vaccine is abrogated in lymphoma patients within the first 12 months following treatment with anti-CD2O antibodies. Haematologica. 2021;107(3):715–720. DOI:10.3324/haematol.2021.279216

 Web of Science ®Google Scholar

Haidar G, Agha M, Bilderback A, et al. Prospective evaluation of COVID-19 vaccine responses across a broad spectrum of immunocompromising conditions: the COVICS study. Clin Infect Dis. 2022;75(1):e630–644. DOI:10.1093/cid/ciac103

 PubMed Web of Science ®Google Scholar

Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood. 2021;137(23):3165–3173. DOI:10.1182/blood.2021011568

 PubMed Web of Science ®Google Scholar

Jinich S, Schultz K, Jannat‐khah D, et al. B cell reconstitution is strongly associated with covid-19 vaccine responsiveness in rheumatic disease patients who received treatment with rituximab. Arthritis Rheumatol. 2021;74(5):776–782. DOI:10.1002/art.42034

 Web of Science ®Google Scholar

König M, Lorentzen ÅR, Torgauten HM, et al. Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations. J Neurol Neurosurg Psychiatry. jnnp-2021. 2021;327612. DOI:10.1136/jnnp-2021-327612.

 Web of Science ®Google Scholar

Kornek B, Leutmezer F, Rommer PS, et al. B cell depletion and sars-COV-2 vaccine responses in neuroimmunologic patients. Ann Neurol. 2022;91(3):342–352. DOI:10.1002/ana.26309

 PubMed Web of Science ®Google Scholar

Kornek B, Leutmezer F., Rommer P.S. et al. SSRN-Distinct patterns of humoral and cellular immune responses following SARS-CoV-2.Pdf. 2022. Vol. 91. pp.342–352. DOI:10.1002/ana.26309.

 Google Scholar

Krasselt M, Wagner U, Nguyen P, et al. Humoral and cellular response to covid-19 vaccination in patients with autoimmune inflammatory rheumatic diseases under real-life conditions. Rheumatology (Oxford). 2022;61(SI2):SI180–188. DOI:10.1093/rheumatology/keac089

 PubMed Web of Science ®Google Scholar

Lim SH, Campbell N., Stuart B., et al. Humoral and cellular responses to SARS-CoV-2 vaccination in patients with lymphoid malignancies. medRxiv. 2021;2021.12.08.21266760. https://doi.org/10.1101/2021.12.08.21266760

 Google Scholar

Madelon N, Lauper K, Breville G, et al. Robust T cell responses in anti-CD20 treated patients following COVID-19 vaccination: a prospective cohort study. Clin Infect Dis. 2021;75(1):e1037–1045. DOI:10.1093/cid/ciab954

 Web of Science ®Google Scholar

Marty PK, Van Keulen VP, Erskine CL, et al. Antigen specific humoral and cellular immunity following sars-cov-2 vaccination in anca-associated vasculitis patients receiving b-cell depleting therapy. Front Immunol. 2022;13:834981.

 PubMed Web of Science ®Google Scholar

Moor MB, Suter-Riniker F, Horn MP, et al. Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigator-initiated, single-centre, open-label study. Lancet Rheumatol. 2021;3(11):e789–797. DOI:10.1016/S2665-9913(21)00251-4

 PubMedGoogle Scholar

Novak F, Nilsson AC, Nielsen C, et al. Humoral immune response following SARS-CoV-2 mRNA vaccination concomitant to anti-CD20 therapy in multiple sclerosis. Mult Scler Relat Disord. 2021;56:103251.

 PubMed Web of Science ®Google Scholar

Perry C, Luttwak E, Balaban R, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with B-cell non-Hodgkin lymphoma. Blood Adv. 2021;5(16):3053–3061. DOI:10.1182/bloodadvances.2021005094

 PubMed Web of Science ®Google Scholar

Schulz E, Hodl I., and Forstner, P. et al. CD19+IgD+CD27− naïve B Cells as predictors of humoral response to COVID-19 mRNA vaccination in immunocompromised patients. medRxiv. 2021;2021.08.11.21261898. https://doi.org/10.1101/2021.08.11.21261898

 Google Scholar

Stefanski AL, Rincon‐arevalo H., Schrezenmeier E. et al. B cell numbers predict humoral and cellular response upon SARS-CoV-2 vaccination among patients treated with rituximab. Arthritis Rheumatol. 2021;74:934–947. https://doi.org/10.1002/art.42060

 Web of Science ®Google Scholar

Tanguay M, Boutin M, Laumaea A, et al. B-cell cytopenia and time to last B-cell-depleting therapy predict response to SARS-COV-2 vaccines in patients with lymphoproliferative disorders. Vaccine. 2022;40(9):1203–1207. DOI:10.1016/j.vaccine.2022.01.040

 PubMed Web of Science ®Google Scholar

Tvito A, Ronson A, Ghosheh R, et al. Anti-CD20 monoclonal antibodies inhibit seropositive response to Covid-19 vaccination in non-Hodgkin lymphoma patients within 6 months after treatment. Exp Hematol. 2022;107:20–23.

 PubMed Web of Science ®Google Scholar