Analysis of the Humoral and Cellular Response After the Third COVID-19 Vaccination in Patients With Autoimmune Hepatitis

Johannes Hartl; Darius Ferenc Rüther; Paul Maria Duengelhoef; Thomas Theo Brehm; Silja Steinmann; Jan Philipp Weltzsch; Fabian Glaser; Martina Sterneck; Marcial Sebode; Christina Weiler-Normann; Marc Lütgehetmann; Golda Melina Schaub; Friedrich Haag; Christoph Schramm; Julian Schulze zur Wiesch; Ansgar Wilhelm Lohse

Disclosures

Liver International. 2023;43(2):393-400.

Abstract and Introduction

Abstract

Background & Aims: To explore the humoral and T-cell response to the third COVID-19 vaccination in autoimmune hepatitis (AIH).

Methods: Anti-SARS-CoV-2 antibody titers were prospectively determined in 81 AIH patients and 53 healthy age- and sex-matched controls >7 days (median 35) after the first COVID-19 booster vaccination. The spike-specific T-cell response was assessed using an activation-induced marker assay (AIM) in a subset of patients.

Results: Median antibody levels were significantly lower in AIH compared to controls (10 908 vs. 25 000 AU/ml, p < .001), especially in AIH patients treated with MMF (N = 14, 4542 AU/ml, p = .004) or steroids (N = 27, 7326 AU/ml, p = .020). Also, 48% of AIH patients had antibody titers below the 10% percentile of the healthy controls (9194 AU/ml, p < .001). AIH patients had a high risk of failing to develop a spike-specific T-cell response (15/34 (44%) vs. 2/16 (12%), p = .05) and showed overall lower frequencies of spike-specific CD4 + T cells (median: 0.074% vs 0.283; p = .01) after the booster vaccination compared to healthy individuals. In 34/81 patients, antibody titers before and after booster vaccination were available. In this subgroup, all patients but especially those without detectable/low antibodies titers (<100 AU/ml) after the second vaccination (N = 11/34) showed a strong, 148-fold increase.

Conclusion: A third COVID-19 vaccination efficiently boosts antibody levels and T-cell responses in AIH patients and even seroconversion in patients with the absent immune response after two vaccinations, but to a lower level compared to controls. Therefore, we suggest routinely assessing antibody levels in AIH patients and offering additional booster vaccinations to those with suboptimal responses.

Introduction

Various reports show a reduced immune response to COVID-19 vaccinations in patients on immunosuppression,^[1] including liver transplant recipients.^[2] Moreover, we have reported recently that AIH patients show an impaired B- and T-cell response after the second COVID-19 vaccination, even in the absence of or under mild immunosuppressive treatment.^[3] Also, AIH patients seemed to have an increased risk to acquire SARS-CoV-2 infection.^[3] At the same time, immunosuppressive drugs^[4,5] and advanced stages of chronic liver diseases^[6] are associated with a more severe course of COVID-19. Additionally, various SARS-CoV-2 variants have been identified as being partly resistant to antibody-mediated neutralization requiring induction of higher antibody titers for protection.^[5–7] Indeed, the third dose of a COVID-19 vaccine demonstrated effectiveness for boosting the vaccination response and preventing severe outcomes in the general population and patients under immunosuppression like solid organ transplant recipients or patients with a rheumatic disease.^[8–10]

In this prospective observational study, we aimed to explore the humoral and T-cell response after the third COVID-19 vaccination in patients with AIH compared to healthy controls in a real-world setting.

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Table 1. Baseline characteristics and immune response to COVID-19 booster vaccination
	AIH (N = 81)	Controls (N = 53)	p
1A: Total cohort (N = 134)
Age (median years, IQR)	60 (52–68)	57 (55–60)	.051
Females (n, %)	67 (83)	42 (79)	.614
Time third vacc.—follow-up (median days, IQR)	35 (26–55)	33 (23–42)	.156
Abs levels RBD (median AU/ml, IQR)	10 908 (4748–20 042)	25 000 (19 047–25 000)	<.001
Seroconversion (n, %)	81 (100)	53 (100)	1.000
≥100 AU/ml (n, %)	79 (98)	53 (100)	.518
≥1000 AU/ml (n, %)	77 (95)	53 (100)	.152
≥9194 AU/ml (n, %)	42 (52)	48 (91)	<.001
≥19 047 AU/ml (n, %)	23 (28)	40 (75)	<.001
T-cell response with SI > 2 (n/N, %)	19/34 (56)	14/16 (88)	.053
1B: AIH patients (N = 81)
BMI (median kg/m², IQR)	25.7 (22.1–30.5)
Creatinine (median mg/dl, IQR)	0.8 (0.7–0.9)
GFR (median ml/min, IQR)	86 (74–96)
HbA1c (median %, IQR)	5.6 (5.2–6.1)
Diabetes (n, %)	12 (15)
Arterial hypertension (n, %)	27 (33)
Cirrhosis (n, %)	19 (23)
IgG (median g/L, IQR)	12.8 (10.1–16.9)
GOT (median U/L, IQR)	35 (27–49)
GPT (median U/L, IQR)	27 (20–47)
Lymphocytes (median 10⁹/L, IQR)	1.37 (0.98–1.73)
T-lymphocytes (median/µl, IQR)	992 (739–1273)
B-lymphocytes (median/µl, IQR)	64 (43–113)
Immunosuppression (n, %)	73 (90)
Steroids (n, %)	27 (31)
If yes, dosage (median mg, range)	5 (5–20)
Azathioprine (n, %)	50 (62)
If yes, dosage (median mg, range)	75 (25–175)
MMF (n, %)	14 (17)
If yes, dosage (median mg, range)	1500 (1000–2000)

Note: Abbreviations: Abs, antibodies; AIH, autoimmune hepatitis; AU, arbitrary units; BMI: body mass index, GFR: glomerular filtration rate, GOT: glutamic oxaloacetic transaminase, GPT: glutamic pyruvic transaminase, IQR: interquartile range, MMF: mycophenolate mofetil, RBD: receptor-binding domain, SI: Stimulation index, UDCA: ursodeoxycholic acid Statistical analysis was performed by Mann–Whitney test and Pearson Chi²-test.

Table 2. Antibody levels in dependence on the presence of potential risk factors
	Yes, AU/ml	No, AU/ml	p
Age > 65 years (n = 25/81)	8859 (4181–19 243)	11 933 (6381–20 126)	.549
Female (n = 67/81)	9187 (4717–19 285)	14 702 (4808–25 000)	.323
Cirrhosis (n = 19/81)	8859 (2607–20 210)	11 525 (5574–20 137)	.526
Diabetes (n = 12/81)	8692 (3391–22 090)	11 525 (4748–20 042)	.800
Arterial hypertension (n = 27/81)	14 792 (7595–22 588)	7985 (4173–17 619)	.031
Immunosuppression (n = 73/81)	8859 (4652–17 693)	25 000 (19377–25 000)	.005
Steroids (n = 27/81)	7326 (4305–12 341)	14 017 (4763–22 573)	.020
Prednisolone (n = 13/81)	4882 (2377–8093)	12 706 (6381–21 523)	.014
Prednisolone mono (n = 3/13)	3246 (2607-X)	5734 (1913–7709)	1.000
≥7.5 mg/d prednisolone (n = 5/13)	2607 (1120–13 472)	5734 (3511–7174)	.622
Azathioprine (n = 50/81)	12 437 (6240–19 957)	8122 (3246–22 058)	.559
Azathioprine mono (n = 36/50)	13 496 (6052–20 352)	7588 (5314–12 641)	.096
>100 mg/days (n = 7/36)	13 359 (10 908–16 045)	13 633 (4642–21 149)	.815
MMF (n = 14/81)	4542 (1224–8144)	12 936 (6624–21 978)	.004
MMF mono (n = 9/14)	4305 (1299–8204)	4778 (941–13 715)	.898
>1000 mg/days (n = 5/9)	4778 (1898–16 161)	4401 (401–16 500)	.730
Combined immunosuppression (n = 28/81)	10 356 (5254–24 763)	10 908 (4652–19 209)	.746
Prednisolone + MMF (n = 3/28)	4305 (1214-X)	12 341 (6653–25 000)	.041
UDCA (n = 25/81)	7322 (4800–16 673)	12 341 (4586–22 568)	.391

Note: Statistical analysis was performed by Mann–Whitney test.
Abbreviations: AIH, autoimmune hepatitis, AU, arbitrary units, IQR, interquartile range, MMF, mycophenolate mofetil, RBD, receptor-binding domain, UDCA, ursodeoxycholic acid.

Table 3. Risk of AIH patients of antibody levels <10% of controls (9194 AU/ml) after a third SARS-CoV-2 vaccination based on the RBD immunoassay
	Univariate OR (95% CI)	p	Multivariate OR (95% CI)	p
Total cohort
Age, years	1.00 (0.97–1.03)	.994
Sex, female (n = 109)	0.95 (0.38–2.42)	.921
Days after third vaccination	1.01 (0.99–1.03)	.172
IS	7.60 (0.89–64.92)	.064
Patients only
Age, years	0.99 (0.96–1.02)	.627
Sex, female (n = 67)	0.54 (0.16–1.78)	.310
Days after third vaccination	1.01 (0.99–1.03)	.495
Cirrhosis (n = 19)	1.31 (0.47–3.68)	.608
BMI, kg/m²	0.97 (0.88–1.07)	.572
Diabetes (n = 12)	1.09 (0.32–3.72)	.889
Hypertension (n = 27)	0.40 (0.15–1.05)	.062
IS (n = 73)	7.60 (0.89–64.92)	.064
Steroids (n = 27)	4.04 (1.50–10.91)	.006
Prednisolone (n = 13)	7.86 (1.62–38.23)	.011	7.30 (1.29–41.23)	.024
Predni mono (n = 3)	3.42 (0.34–34.32)	.297
Predni ≥ 7.5 mg/days (n = 5)	4.69 (0.50–43.89)	.176
Budesonide (n = 14)	1.40 (0.35–5.63)	.638
MMF (n = 14)	5.11 (1.30–20.01)	.019	4.75 (1.01–22.36)	.049
MMF mono (n = 9)	4.38 (0.85–22.53)	.078
MMF > 1 g/day (n = 5)	3.64 (0.69–19.23)	.129
Azathioprine (n = 50)	0.52 (0.21–1.30)	.162
Aza mono (n = 36)	0.33 (0.13–0.83)	.019	0.84 (0.27–2.55)	.836
Aza > 100 mg/day (n = 7)	0.27 (0.05–1.39)	.117
Combined IS (n = 28)	1.12 (0.45–2.80)	.808
Predni + MMF (n = 3)	n.a.
UDCA (n = 25)	1.64 (0.63–4.26)	.306
HbA1c, %	1.71 (0.73–4.01)	.215
eGFR, ml/min	0.99 (0.97–1.02)	.578
IgG, g/L	0.93 (0.85–1.01)	.085
Lymphocytes, 10⁹/L	0.79 (0.35–1.79)	.575

Abbreviations: AIH, autoimmune hepatitis; AU, arbitrary units; BMI: body mass index, CI: confidence interval, eGFR: estimated glomerular filtration rate, IS, Immunosuppression, MMF, mycophenolate mofetil, OR, odds ratio, RBD, receptor-binding domain; UDCA: ursodeoxycholic acid.

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Analysis of the Humoral and Cellular Response After the Third COVID-19 Vaccination in Patients With Autoimmune Hepatitis

Abstract and Introduction

Abstract

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