Effectiveness of SARS-CoV-2 vaccination in liver transplanted patients: The debate is open!

To the Editor:

Data about the immunogenicity of SARS-CoV-2 vaccination in solid organ transplant recipients are lacking. This population was excluded from clinical trials and lower response to vaccination is a well-known problem in immunocompromised solid organ recipients. In this scenario, we read with great interest the article “Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients” by Rabinowich L. et al. recently published in Journal of Hepatology evaluating the immunogenicity of the Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine in liver transplant (LT) recipients. They showed that only 47.5% of patients developed neutralizing antibody titers, 10-20 days after receiving the second dose. Similar results have been described in recent reports on SARS-CoV-2 vaccination in solid organ transplant recipients.[2], [3], [4]

We would like to share our preliminary results about a prospective study evaluating the effectiveness of SARS-CoV-2 vaccination (in terms of immunogenicity and safety) in a cohort of adult liver transplanted patients regularly followed up at 2 referral hospitals in Southern Italy (Cardarelli Hospital and Federico II Academic Hospital). All liver transplanted recipients had stable graft function prior to vaccination. Participants signed written informed consent. The study was approved by the Federico II Institutional Review Board (n. 214/2021). No patient transplanted during the COVID-19 pandemic received a liver from a SARS-CoV-2-positive donor; however, information about previous SARS-CoV-2 infection in the donors was not available. We enrolled 365 LT patients undergoing Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccination. All patients had a negative history for COVID-19 and tested negative for anti–SARS-CoV-2 antibodies in the 7 days preceding the first dose injection. Four weeks after the second vaccine dose, blood samples were collected for analysis of anti-Spike protein IgG using LIAISON SARS-CoV-2 S1/S2-IgG chemiluminescent assay (DiaSorin, Italy) (range < 3.8 to >400 AU/ml [positive ≥25 AU/ml]). The vaccination was well tolerated, and no major adverse events occurred in any of the enrolled patients. Protective levels of antibodies were detected in 273/365 patients (74.8%) with a mean value of 214.79 ± 143 AU/ml. In the 92 patients with negative serology, statistically significant associated factors were: older age (>65 years), higher BMI, shorter time from transplantation and immunosuppressive regimens with multiple drugs and antimetabolite therapy (see Table 1 for details). These preliminary results are partially in line with Rabinowich et al. who reported negative serologic response in older patients (>63 years), those receiving a high dose of prednisone in the past 12 months, and regimens including antimetabolites and triple immunosuppressive therapy. Furthermore, we compared the serology of LT patients with a control group of 340 healthcare workers with no major comorbidities matched for age and sex (mean age 57.86 ± 8.28; 64% males). In the control group only 5/340 (1.4% vs. 26.2%) showed a negative serology 4 weeks after full vaccination, and mean antibodies levels were 314.32 ± 94.1 AU/m, which was statistically higher than in the LT group (p <0.0001).

Table 1

Characteristics of LT recipients stratified according to the serologic response after 2 doses of the BioNTech BNT162b2 SARS-CoV-2 vaccine.

Characteristics	Overall (n = 365)	SARS-CoV-2 seronegative (n = 92)	SARS-CoV-2 seropositive (n = 273)	p value
Age, years (mean ± SD)	62.52 ± 12.97	65.01 ± 9.32	61.68 ± 13.9	<0.0001∗
<40 years, n (%)	28 (7.6%)	1 (1.08%)	27 (9.8%)	<0.0001∗∗
40-65 years, n (%)	150 (41.1%)	43 (46.7%)	107 (39.2%)	0.071∗∗
>65 years, n (%)	187 (51.23%)	48 (52.17%)	139 (50.9%)	0.036∗∗
Male, sex, n (%)	279 (76.4%)	73 (79.3%)	206 (75.4%)	0.06∗∗
BMI, kg/m2 (mean ± SD)	26.56 ± 4.52	27.7 ± 7.09	26.77 ± 4.59	0.031∗
Time from transplantation, years (mean ± SD)	14.08 ± 8.84	11.94 ± 8.72	14.79 ± 8.77	<0.001∗
<1 year, n (%)	7 (1.91%)	5 (5.4%)	2 (0.7%)	<0.0001∗∗
1-5 years, n (%)	69 (18.9%)	22 (23.9%)	47 (17.21)	0.0025∗∗
5-10 years, n (%)	58 (15.89%)	15 (16.3%)	43 (15.75%)	0.058∗∗
>10 years, n (%)	231 (63.21%)	50 (54.3%)	181 (66.3%)	<0.0001∗∗
Immunosuppressive therapy, n (%)
Calcineurin inhibitor	299 (81.9%)	72 (78.3%)	227 (83.1%)	0.19∗∗
Antimetabolite	132 (36.2%)	49 (53.3%)	83 (30.4%)	<0.0001∗∗
mTOR inhibitor	85 (23.3%)	30 (32.6%)	55 (20.1%)	0.021∗∗
Single immunosuppressive agent, n (%)	218 (59.7%)	34 (36.9%)	184 (67.3%)	<0.0001∗∗
Two or more immunosuppressive agents, n (%)	147 (40.3%)	58 (63.1%)	89 (32.7%)	<0.0001∗∗
Steroids, n (%)	28 (7.6%)	9 (9.8%)	19 (6.9%)	0.07∗∗

LT, liver transplantation.

Kruskal-Wallis test.

Chi squared, Fisher exact test

Our results highlight the decreased humoral response in LT recipients. Moreover, we define the most vulnerable individuals among them (i.e., older, overweight/obese patients, and those receiving multiple drug immunosuppressive regimens and regimens including antimetabolites). Even if these findings were expected, given the known scarce antibody response to other vaccines in immunocompromised patients, we are continuing our study to obtain data about the long-term effectiveness and immunogenicity of SARS-CoV-2 vaccination and the impact of an additional dose, as recently suggested by Werbel et al.

Financial support

No source of funding to declare.

Authors’ contributions

M.G., IE, V.C. made substantial contributions to the conception and the design; MG wrote the article; A.F. acquired data; F.M. revised the article critically for important intellectual contribution. All authors read and approved the final version of the article.

Conflict of interest

No personal or financial conflicts of interest for all the authors.

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