Anti-SARS-CoV-2 Spike Antibody Response to the Fourth Dose of BNT162b2 mRNA COVID-19 Vaccine and Associated Factors in Japanese Hemodialysis Patients

Figures & data

Figure 1 Study flow chart.

Abbreviation: COVID-19, coronavirus disease 2019.

Table 1 Demographic and Clinical Characteristics

	Hemodialysis Patients (n=51)
Age (year)	70.7 ± 12.5
Male sex (number, %)	31 (60.8%)
Body mass index (kg/m^2)	22.6 ± 4.2
Hemodialysis vintage (year)	4.0 [2.0–8.0]
Past or current smoking (number, %)	10 (19.6%)
Alcohol drinking (number, %)	11 (21.6%)
Hypertension (number, %)	32 (62.7%)
Diabetes mellitus (number, %)	22 (43.1%)
Autoimmune disease (number, %)	6 (11.8%)
Allergic disease (number, %)	15 (29.4%)
Previous hepatitis B virus infection (number, %)	8 (15.7%)
Previous hepatitis C virus infection (number, %)	2 (3.9%)
Previous syphilis infection (number, %)	3 (5.9%)
Renin–angiotensin system inhibitor (number, %)	17 (33.3%)
Statin (number, %)	16 (31.4%)
Erythropoiesis-stimulating agent (number, %)	44 (86.3%)
Hypoxia-inducible factor prolyl hydroxylase inhibitor (number, %)	4 (7.8%)
Iron supplement (number, %)	29 (56.9%)
Zinc supplement (number, %)	4 (7.8%)
Phosphate binder (number, %)	41 (80.4%)
Vitamin D analog (number, %)	40 (78.4%)
Calcimimetic (number, %)	19 (37.3%)
Corticosteroid (number, %)	3 (5.9%)
Albumin (g/dL)	3.5 ± 0.4
White blood cell count (/μL)	6066 ± 1670
Lymphocyte count (/μL)	1145 ± 378
Hemoglobin (g/dL)	10.7 ± 1.2
Platelet count (×10^4/μL)	18.7 ± 6.1
Blood urea nitrogen (mg/dL)	57.2 ± 14.0
Creatinine (mg/dL)	10.2 ± 2.9
Sodium (mEq/L)	139.2 ± 3.2
Potassium (mEq/L)	4.6 ± 0.6
Chloride (mEq/L)	101.4 ± 3.5
Total calcium (mg/dL)	8.3 ± 0.5
Phosphate (mg/dL)	4.9 ± 1.1
Magnesium (mg/dL)	2.5 ± 0.3
Uric acid (mg/dL)	6.8 ± 1.1
Total cholesterol (mg/dL)	152.5 ± 39.9
C-reactive protein (mg/dL)	0.27 [0.11–0.95]
Intact-parathyroid hormone (pg/mL)	147.8 ± 57.3
β2 microglobulin (mg/L)	28.6 ± 6.3
Ferritin (ng/mL)	256.8 ± 207.7
Transferrin saturation (%)	28.5 ± 21.4
Zinc (μg/dL)	58.8 ± 12.4
Glycated hemoglobin (%)	5.8 ± 0.9
Glycoalbumin (%)	19.5 ± 3.9
Normalized protein catabolism rate (g/kg/day)	0.73 ± 0.20
Single pool Kt/V	1.50 ± 0.27

Abbreviation: Kt/V, urea clearance.

Figure 2 Change in the median anti-SARS-CoV-2 spike antibody titers in hemodialysis patients (n = 51). Values are presented as medians [interquartile ranges].

Notes: *p < 0.001; **p < 0.01.

Abbreviation: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3 Change in the mean anti-SARS-CoV-2 spike antibody titers in hemodialysis patients (n = 51). Values are presented as means ± standard deviations.

Notes: *p < 0.001; **p < 0.005.

Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; NS, not significant.

Table 2 Simple and Multiple Linear Regression Analyses of the Variables Correlated with Log-Anti-SARS-CoV-2 Spike Antibody Titer 4 Weeks After the Fourth BNT162b2 mRNA COVID-19 Vaccination

Variables	Simple Linear Regression Analysis		Multiple Linear Regression Analysis
	Standard Coefficient	P value	Standard Coefficient	P value
Age (year)	−0.176	0.22
Male sex (yes vs no)	0.249	0.08
Body mass index (kg/m^2)	0.166	0.24
Log-hemodialysis vintage (year)	−0.281	0.046	−0.025	0.74
Past or current smoking (yes vs no)	0.223	0.12
Alcohol drinking (yes vs no)	0.127	0.37
Diabetes mellitus (yes vs no)	−0.034	0.81
Hypertension (yes vs no)	0.012	0.93
Allergic disease (yes vs no)	0.123	0.39
Autoimmune disease (yes vs no)	−0.145	0.31
Previous hepatitis B virus infection (yes vs no)	0.013	0.93
Previous hepatitis C virus infection (yes vs no)	0.116	0.42
Previous syphilis infection (yes vs no)	−0.212	0.14
Corticosteroid (yes vs no)	−0.048	0.74
Renin–angiotensin system inhibitor (yes vs no)	0.081	0.57
Statin (yes vs no)	0.069	0.64
Erythropoiesis-stimulating agent (yes vs no)	−0.282	0.045	0.087	0.31
Hypoxia-inducible factor prolyl hydroxylase inhibitor (yes vs no)	0.306	0.029	0.217	0.011*
Iron supplement (yes vs no)	−0.075	0.61
Zinc supplement (yes vs no)	−0.180	0.21
Phosphate binder (yes vs no)	−0.106	0.46
Vitamin D analog (yes vs no)	−0.070	0.63
Calcimimetic (yes vs no)	0.030	0.83
Albumin (g/dL)	0.002	0.99
White blood cell count (/μL)	0.139	0.33
Lymphocyte count (/μL)	0.078	0.59
Hemoglobin (g/dL)	0.172	0.23
Platelet count (×10^4/μL)	0.005	0.97
Blood urea nitrogen (mg/dL)	−0.213	0.13
Creatinine (mg/dL)	0.018	0.90
Sodium (mEq/L)	−0.149	0.30
Potassium (mEq/L)	−0.209	0.14
Chloride (mEq/L)	0.020	0.89
Total calcium (mg/dL)	−0.080	0.58
Phosphate (mg/dL)	−0.042	0.77
Magnesium (mg/dL)	−0.073	0.61
Uric acid (mg/dL)	−0.148	0.30
Total cholesterol (mg/dL)	−0.220	0.12
Log-C-reactive protein (mg/dL)	0.131	0.36
Intact-parathyroid hormone (pg/mL)	0.186	0.19
β2 microglobulin (mg/L)	−0.035	0.81
Ferritin (ng/mL)	−0.112	0.43
Transferrin saturation (%)	−0.079	0.58
Zinc (μg/dL)	0.002	0.99
Glycated hemoglobin (%)	0.268	0.20
Glycoalbumin (%)	0.125	0.55
Normalized protein catabolism rate (g/kg/day)	−0.219	0.12
Single pool Kt/V	−0.379	0.006	−0.102	0.18
Log-anti-SARS-CoV-2 spike antibody titer 1 week before the fourth BNT162b2 mRNA COVID-19 vaccination (AU/mL)	0.858	<0.001	0.810	<0.001*

Note: *p<0.05.

Abbreviations: COVID-19, coronavirus disease 2019; Kt/V, urea clearance; Log, logarithm; mRNA, messenger RNA; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Table 3 Simple and Multiple Linear Regression Analyses of the Variables Correlated with Log-Anti-SARS-CoV-2 Spike Antibody Titer 12 Weeks After the Fourth BNT162b2 mRNA COVID-19 Vaccination

Variables	Simple Linear Regression Analysis		Multiple Linear Regression Analysis
	Standard Coefficient	P value	Standard Coefficient	P value
Age (year)	−0.052	0.72
Male sex (yes vs no)	0.250	0.08
Body mass index (kg/m^2)	0.057	0.69
Log-hemodialysis vintage (year)	−0.264	0.06
Past or current smoking (yes vs no)	0.153	0.29
Alcohol drinking (yes vs no)	0.121	0.40
Diabetes mellitus (yes vs no)	0.147	0.31
Hypertension (yes vs no)	0.071	0.62
Allergic disease (yes vs no)	0.101	0.48
Autoimmune disease (yes vs no)	−0.114	0.43
Previous hepatitis B virus infection (yes vs no)	0.165	0.25
Previous hepatitis C virus infection (yes vs no)	0.056	0.69
Previous syphilis infection (yes vs no)	−0.254	0.07
Corticosteroid (yes vs no)	−0.067	0.64
Renin–angiotensin system inhibitor (yes vs no)	0.082	0.57
Statin (yes vs no)	−0.021	0.89
Erythropoiesis-stimulating agent (yes vs no)	−0.262	0.06
Hypoxia-inducible factor prolyl hydroxylase inhibitor (yes vs no)	0.218	0.12
Iron supplement (yes vs no)	0.038	0.79
Zinc supplement (yes vs no)	−0.201	0.16
Phosphate binder (yes vs no)	−0.091	0.53
Vitamin D analog (yes vs no)	−0.077	0.59
Calcimimetic (yes vs no)	−0.070	0.62
Albumin (g/dL)	−0.041	0.77
White blood cell count (/μL)	0.057	0.69
Lymphocyte count (/μL)	0.008	0.95
Hemoglobin (g/dL)	0.152	0.29
Platelet count (×10^4/μL)	−0.047	0.75
Blood urea nitrogen (mg/dL)	−0.339	0.015	−0.015	0.90
Creatinine (mg/dL)	−0.068	0.64
Sodium (mEq/L)	−0.098	0.49
Potassium (mEq/L)	−0.280	0.046	−0.071	0.52
Chloride (mEq/L)	0.089	0.54
Total calcium (mg/dL)	−0.062	0.67
Phosphate (mg/dL)	−0.166	0.24
Magnesium (mg/dL)	0.008	0.96
Uric acid (mg/dL)	−0.185	0.19
Total cholesterol (mg/dL)	−0.146	0.31
Log-C-reactive protein (mg/dL)	0.166	0.24
Intact-parathyroid hormone (pg/mL)	0.112	0.44
β2 microglobulin (mg/L)	−0.096	0.51
Ferritin (ng/mL)	0.025	0.86
Transferrin saturation (%)	−0.116	0.42
Zinc (μg/dL)	−0.045	0.76
Glycated hemoglobin (%)	0.210	0.31
Glycoalbumin (%)	0.095	0.65
Normalized protein catabolism rate (g/kg/day)	−0.282	0.045	−0.070	0.68
Single pool Kt/V	−0.423	0.002	−0.131	0.40
Log-anti-SARS-CoV-2 spike antibody titer 1 week before the fourth BNT162b2 mRNA COVID-19 vaccination (AU/mL)	0.752	<0.001	0.677	<0.001*

Note: *p<0.05.

Abbreviations: COVID-19, coronavirus disease 2019; Kt/V, urea clearance; Log, logarithm; mRNA, messenger RNA; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Table 4 Comparison of Patients’ Characteristics Between Hemodialysis Patients Not Infected with COVID-19 and Those Infected with COVID-19 After the Third or Fourth Dose

	Hemodialysis Patients not Infected with COVID-19 (n=51)	Hemodialysis Patients Infected with COVID-19 After the Third or Fourth Dose (n=12)	P value
Age (year)	70.7 ± 12.5	76.8 ± 14.4	0.14
Male sex (number, %)	31 (60.8%)	5 (41.7%)	0.33
Body mass index (kg/m^2)	22.6 ± 4.2	20.6 ± 3.4	0.15
Hemodialysis vintage (year)	4.0 [2.0–8.0]	3.0 [3.0–12.3]	0.57
Past or current smoking (number, %)	10 (19.6%)	2 (16.7%)	1.00
Alcohol drinking (number, %)	11 (21.6%)	1 (8.3%)	0.43
Hypertension (number, %)	32 (62.7%)	10 (83.3%)	0.31
Diabetes mellitus (number, %)	22 (43.1%)	6 (50.0%)	0.75
Autoimmune disease (number, %)	6 (11.8%)	1 (8.3%)	1.00
Allergic disease (number, %)	15 (29.4%)	7 (58.3%)	0.09
Previous hepatitis B virus infection (number, %)	8 (15.7%)	2 (16.7%)	1.00
Previous hepatitis C virus infection (number, %)	2 (3.9%)	1 (8.3%)	0.48
Previous syphilis infection (number, %)	3 (5.9%)	0 (0.0%)	1.00
Renin–angiotensin system inhibitor (number, %)	17 (33.3%)	7 (58.3%)	0.18
Statin (number, %)	16 (31.4%)	5 (41.7%)	0.51
Erythropoiesis-stimulating agent (number, %)	44 (86.3%)	12 (100.0%)	0.33
Hypoxia-inducible factor prolyl hydroxylase inhibitor (number, %)	4 (7.8%)	0 (0.0%)	1.00
Iron supplement (number, %)	29 (56.9%)	8 (66.7%)	0.75
Zinc supplement (number, %)	4 (7.8%)	0 (0.0%)	1.00
Phosphate binder (number, %)	41 (80.4%)	10 (83.3%)	1.00
Vitamin D analog (number, %)	40 (78.4%)	11 (91.7%)	0.43
Calcimimetic (number, %)	19 (37.3%)	5 (41.7%)	1.00
Corticosteroid (number, %)	3 (5.9%)	0 (0.0%)	1.00
Anti-SARS-CoV-2 spike antibody titer 4 weeks after the second BNT162b2 mRNA COVID-19 vaccination (AU/mL)	2896 [1110–4358]	1606 [608–2531]	0.14
Anti-SARS-CoV-2 spike antibody titer 1 week before the third BNT162b2 mRNA COVID-19 vaccination (AU/mL)	220 [127–411]	188 [127–492]	0.83

Abbreviations: COVID-19, coronavirus disease 2019; mRNA, messenger RNA; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Table 5 Timing of Infection and Clinical Outcome of Hemodialysis Patients Infected with COVID-19 After the Third Dose (A) and the Fourth Dose (B)

(A) Hemodialysis patients infected with COVID-19 after the third dose
Patient Number	Age (Years)	Sex	Timing of Infection	Hospitalization	Clinical Outcome	Anti-SARS-CoV-2 Spike Antibody titer 1 Week Before the Third BNT162b2 mRNA COVID-19 Vaccination (AU/mL)
1	88	Female	1 week after the third dose	Yes	Alive	401
2	86	Female	6 weeks after the third dose	Yes	Death	7
3	66	Male	18 weeks after the third dose	No	Death	198
4	78	Male	19 weeks after the third dose	No	Alive	1078
5	98	Female	22 weeks after the third dose	No	Death	793
6	85	Female	23 weeks after the third dose	No	Alive	85
(B) Hemodialysis patients infected with COVID-19 after the fourth dose
Patient number	Age (Years)	Sex	Timing of Infection	Hospitalization	Clinical Outcome	Anti-SARS-CoV-2 Spike Antibody Titer 1 Week Before the Fourth BNT162b2 mRNA COVID-19 Vaccination (AU/mL)
1	83	Female	4 weeks after the fourth dose	No	Alive	1088
2	89	Male	7 weeks after the fourth dose	No	Alive	531
3	69	Female	8 weeks after the fourth dose	No	Death	13,000
4	50	Male	9 weeks after the fourth dose	No	Alive	1702
5	75	Female	11 weeks after the fourth dose	No	Alive	14,000
6	55	Male	12 weeks after the fourth dose	No	Alive	9540

Abbreviations: COVID-19, coronavirus disease 2019; mRNA, messenger RNA; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.