Efficacy and safety of a fourth dose of the COVID-19 vaccine in kidney transplant recipients: A systematic review and meta-analysis

Abstract

Background

Kidney transplant recipients (KTRs) who become infected with SARS-CoV-2 are at greater risk of serious illness and death than the general population. To date, the efficacy and safety of the fourth dose of the COVID-19 vaccine in KTRs have not been systematically discussed.

Methods

This systematic review and meta-analysis included articles from PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wanfang Med Online published before May 15, 2022. Studies evaluating the efficacy and safety of a fourth dose of the COVID-19 vaccine in kidney transplant recipients were selected.

Results

Nine studies were included in the meta-analysis, with a total of 727 KTRs. The overall pooled seropositivity rate after the fourth COVID-19 vaccine was 60% (95% CI, 49%–71%, I² = 87.83%, p > 0.01). The pooled proportion of KTRs seronegative after the third dose that transitioned to seropositivity after the fourth dose was 30% (95% CI, 15%–48%, I² = 94.98%, p < 0.01).

Conclusions

The fourth dose of the COVID-19 vaccine was well tolerated in KTRs with no serious adverse effects. Some KTRs showed a reduced response even after receiving the fourth vaccine dose. Overall, the fourth vaccine dose effectively improved seropositivity in KTRs, as recommended by the World Health Organization for the general population.

1. Introduction

The coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has affected billions of people worldwide [1,2]. In the absence of effective treatment options, research on preventive vaccines has been the focus of numerous countries. The advent of the neocrown vaccine has dramatically reduced COVID-19-related mortality and the prevalence of severe diseases, and the vast majority of the population has benefited from it [[3], [4], [5], [6], [7]]. However, most clinical trials of the new crown vaccine have excluded specific individuals, including kidney transplant recipients (KTRs). This is compounded by the fact that kidney transplant patients infected with SARS-CoV-2 are at greater risk of serious illness and death than the general population. Specifically, higher mortality was observed in KTRs hospitalized for COVID-19, with an increased risk primarily due to the high comorbidity burden and advanced ages of patients rather than issues related to immunosuppression [[8], [9], [10], [11]].

Researchers are aware of the importance of the protective properties of the new crown vaccine in special populations, and several clinical studies have investigated the immunogenicity and safety of COVID-19 basal and first-booster (third dose) vaccines in KTRs. Grupper et al. analyzed the humoral immune response in 136 KTRs and compared it with a control group of 25 patients vaccinated with the BNT1622b2 vaccine (Pfizer). Only 51 of the 136 KTRs (37.5%) showed a positive antibody response, compared to 100% seropositivity in the control group [12]. Only 29/49 (59%) KTRs had sera containing neutralizing antibodies against wild-type SARS-CoV-2 or the B16172 (Delta) variant, resulting in significantly lower neutralizing titers compared to healthy controls (p < 0.001) [13]. This reduced antibody response in KTRs is worrisome and indicates that new preventive measures to protect renal transplant patients are required. Clinical studies of a second booster vaccine (fourth dose) in KTRs have been conducted in the United States [14], France [[15], [16], [17], [18]], Germany [[19], [20], [21]], and Norway [22]; further, Osmanodja et al. tested a fifth dose in KTRs who had an unsatisfactory serologic response after the first four vaccine doses [19]. These studies gave poor results regarding the seropositivity rate. For example, only 10% of the patients who did not respond (<1 binding antibody units (BAU)/ml) after the third dose achieved anti-spike IgG titers above 143 BAU/mlafter the fourth dose.

A meta-analysis showed that an antibody response occurred in 6.4–69.2% of solid organ transplant recipients following their third COVID-19 vaccine dose. The pooled proportion of antibody response rate after the third vaccine was 50.3% (95% confidence interval (CI): 37.1–63.5, I ² = 90%) [23].To our knowledge, no systematic evaluation and meta-analysis assessing the efficacy and safety of the fourth dose of the COVID-19 vaccine in KTRs has been performed.

2. Objective/hypothesis

We aimed to perform a meta-analysis to evaluate the published data on the efficacy and safety of a second booster dose (fourth dose) of the SARS-CoV-2 vaccine in KTRs.

3. Methods

3.1. Literature search strategy and eligibility criteria

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [24]. Before commencing the study, the protocol was registered in PROSPERO, a prospective international register of systematic reviews (CRD42022334104). The PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wanfang Med Online databases were searched for articles published until May 15, 2022 (Supplementary Table S1). The search keywords included: (“four doses,” “fourth dose,” “booster,” “fourth-dose,” “4th dose,” “4 doses,” “boost vaccination,” or “four-dose”) and (“COVID -19 Vaccines,” “SARS-CoV-2 Vaccines,” “coronavirus Disease 2019 Virus Vaccine,” “2019-nCoV Vaccine,” “2019 Novel Coronavirus Vaccine,” “messenger RNA vaccine,” “messenger RNA-based vaccines,” “Pfizer,” “mRNA-1273,” “BioNTech,” or “anti-SARS-CoV-2”). The other terms used included “kidney transplantation,” “renal transplantation,” “kidney grafting,” or “organ-transplant recipients.”

Studies evaluating the efficacy of a fourth dose of the COVID-19 vaccine in KTRs were included, while studies on KTRs with a previous COVID-19 infection or highly positive serology prior to the fourth vaccination were excluded. Only studies published in English or Chinese were included in the final analysis. All records returned from the searches were extracted using EndNote® software, and duplicates were removed. Two authors (Yasen Kuniduzi and Bo Chen) independently screened the titles and abstracts to identify potentially relevant studies. If no consensus was reached based on the abstract or if the abstract did not contain sufficient information, the full-text article was reviewed. Disagreements between the reviewers regarding study inclusion at this stage were resolved by a third reviewer (Shoyong Xu). Finally, the references of the included studies were screened to identify additional relevant studies. For serial studies, only the most recent publications were included to avoid repeated inclusion of the same literature.

3.2. Outcome measurement and data extraction

The primary outcome sought was the seropositivity rate in KTRs after the fourth COVID-19 vaccine. Seroconversion was assessed in each study according to the manufacturer's threshold values of COVID-19-specific antibodies. Two authors (Yasen Kuniduzi and Bo Chen) extracted data using standardized data extraction tables. The extracted data included the following information: first author; publication date; study location; study design; the total number of participants; demographic information, including the median age and sex ratio; immunosuppression status; time since transplant; type of third vaccine received; the time between the third and fourth vaccines; type of fourth vaccine received; antibody titer before the fourth dose; time from the fourth vaccine to outcome measurement; primary outcome measurement technique; percentage of patients with seroconversion to the fourth vaccine dose; and other relevant outcomes, when available. Any disagreements were resolved via consensus with a third author (Shoyong Xu).

3.3. Risk of bias assessment

The quality of evidence in the nine included studies was evaluated according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria, which describes the degree of confidence in the quality and strength of recommendation [25]. In addition, the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool was used to assess the risk of bias [26]. Two reviewers (Yasen Kuniduzi and Bo Chen) independently evaluated each study using the GRADE and ROBINS-I frameworks, and any disagreements were resolved by a third author (Shoyong Xu).

3.4. Statistical analyses

A random-effects meta-analysis was performed to estimate the pooled proportions and 95% confidence intervals (95% CIs). The I ² statistic was used to assess the heterogeneity of the pooled estimate, where values ≥0.5 were considered substantially heterogeneous. Statistical analyses were performed using Stata version 17.0. The “metaprop” command was used to transform the data using the double inverse sine method, and fixed and random effects models were used to combine the effect sizes. Sensitivity analysis was conducted using the leave-one-out random-effects DerSimonian-Laird model. Heterogeneity between studies was defined as low (I ² = 0–25%), moderate (I ² = 26–75%), or high (I ² > 75%) [27]. A Galbraith diagram was used for heterogeneity testing. Funnel plots were used to report the publication bias. The contribution of each risk factor to the response to the fourth vaccination dose was evaluated using subgroup and leave-one-out analyses,p value <0.05 was considered as significant.

4. Results

4.1. Literature search

In total, 904 potential records were identified in the literature. Duplicates (n = 72) were removed before screening, and 796 records were excluded because they were irrelevant to the subject after scanning the title or abstract. Subsequently, 36 studies underwent a full-text review, of which only nine studies [[14], [15], [16], [17], [18], [19], [20], [21], [22]] (including two studies identified through other sources) were assessed for eligibility and included in the final meta-analysis (Fig. 1 ). The extracted data are summarized in Table 1 and Table 2 .

Fig. 1.

Flow of articles through the review. WOS=Web of Science, CNKI=China National Knowledge Infrastructure.

Table 1.

Main characteristics of included articles.

Author Year	Country	Design	No	no serological response (%)	Males (%)	Age Median/Mean (Range/SD)	Time from Transplantation (Median, IQR)	name of vaccine(3rd)	Type of vaccine(3rd)	Time from 3rd to 4th Dose	Antibody Titer before 4th Dose
Alejo, J.L 2021	USA	Prospective	7	71.4	42.8	53.3 (±7.57)	7.94 (±6.83) years	Pfizer 57.1% Moderna 42.9%	mRNA	28 (21−30) days	<50 U/ml or < 4 AU
Kamar, N 2021	France	Retrospective	25	96	/	/	/	Moderna	mRNA	65 days	/
Benotmane, I 2022	France	Retrospective	67	13.4	61.2	56.6 (47–64)	6.1 (2.2–11.4) years	Moderna	mRNA	68(63–82) days	13(2.6–66.3) BAUs/ml
Masset, C 2022	France	Retrospective	49	100	47	63	/	/		30 days	<1BAU/ml
Osmanodja, B 2022	Germany	Retrospective	250	100	67	61(51–70)	7.7 (3.0–12.7) years	mRNA 72.8%	mRNA	64 (55–84) days	29.4%
Caillard, S 2022	France	Retrospective	92	0	69.5	55.9(47.1–64.2)	5.5 (2.3–11.4) years	–	–	68(61–74.7) days	16.4(5.9–62.3) BAU/ml
Midtvedt, K 2022	Norway	Retrospective	188	54.3	58%	60 ± 12	8.3 ± 7.0 years	Pfizer 91% Moderna 9%	mRNA	126(68–128)days	4.6 (2.5–32) BAU/ml
Schrezenmeier, E 2022	Germany	Retrospective	29	51.7	58.6	59.48(14.8)	9.9 (5.9) years	mRNA 48.3% mixed mRNA 51.7%	mRNA	59.1(47–71)days	/
Roch, T 2022	Germany	Retrospective	20	65	70	64.6 ± 10.07	97.8 (7.5) month	Pfizer	mRNA	> 28 days	<0.80 U/ml Negative 65% low median titer 3.7 [0.6–35.9] 35%

Table 2.

Efficacy and safety of the fourth dose of COVID-19 vaccine among KTRs (After 4th dose).

Author (Year)	Primary Outcome	Name of vaccine(4th)	Type of vaccine(4th)	Time from 4th to Outcome Measuring	Primary Outcome Measuring Technique	Seropositive Rate (%)	Secondary Outcome	Secondary Outcome Results	Factors Associated with Reduced Response	Safety
Alejo, J.L (2021)	Serologic response	Pfizer 28.6% Moderna42.8% J&J 28.6%	mRNA 71.4% Adenovirus vector 28.6%	2–6 weeks	Roche (n = 5) ELISA (n = 2)	57.10%				No serious adverse event or acute rejection episode
Kamar, N (2021)	Serologic response	Pfizer 100%	mRNA	–	ELISA	56.00%	Interferon (IFN)–γ produced by specific SARS-CoV-2 T cells	167.5 SFUs per 106 PBMCs among seropositive patients and 55 SFU per 106 PBMC among seronegative patients		No serious adverse event or acute rejection. One patient presented with a recurrence of IgA nephropathy. One patient indicated gastrointestinal symptoms. Four patients presented with fatigue. myalgia.
Benotmane, I (2022)	Serologic response	Moderna 100%	mRNA	One month	Abbott	88.06%	1. Median anti-RBD titer 2.Median ID50 titers 3.Neutralizing antibodies against the Delta strain	1. Increased significantly from 13 to 112.5 BAUs/ml 2.Increased from <7.5 to 47.1 BAUs/ml 3.From 16% raised to 66%		Neither major adverse events nor graft rejections were observed. One patient developed symptomatic COVID-19 caused by the Delta variant 19 days after the fourth dose.
Masset, C (2022)	Serologic response	Pfizer 100%	mRNA	35 days	NA	42.86%	1.Antibody titer concentration 2.Neutralizing	1. Mean titer 82 BAU/ml 2.4 of 49 had a high BAU titer (>264/ml)	1.Lower steroid use 2. Less lymphopenia 3. Longer time between the third and fourth dose 4. Larger utilization of the BNT162b vaccine	SARS-CoV-2 infection occurred in 1 patient, who previously developed a low humoral response following 4 injections
Osmanodja, B (2022)	Serologic response	–	mRNA 86.8%	A minimum of 14 days	ELISA	55.60%	Cumulative serological response	74.2%	Belatacept treatment and higher MPA dose	No serious adverse events or acute rejections
Caillard, S (2022)	Serologic response	Pfizer 40.0% Moderna 60.0%	mRNA	29(26–34) days	NA	50%	Median antispike IgG	145(27.6 ‐243) BAU/ml		No safety concerns with the fourth vaccine dose.
Midtvedt, K (2022)	Serologic response	Moderna 100%	mRNA	1 month	NA	63.30%			Antibody level and renal function at time of vaccination	No serious adverse events or acute rejections
Schrezenmeier E (2022)	Serologic response	Pfizer 100%	mRNA	28–35 days	ELISA	75.86%	1.IgA positive 2.Neutralization capacity	1.11/21(52.2%) 2.15/21 (71.4%)		Graft function remained stable and no rejection episodes
Roch, T (2022)	Serologic response	J&J 100%	Adenovirus vector	34.65 days	Roche	45%	1.Antibody titer 2.Neutralization assay 3.The functional SARS-CoV-2–reactive CD4 and CD8 T-cell response	1. 50.0 [11.3–342.9] 2. WT SARS-CoV-2 strain 3/9 (33.3%) delta VOC 4/9(44.4%) 3.Enhanced 30% to 60%

4.2. Study characteristics

Details of the included studies (n = 9) are presented in Table 1. Most studies (n = 7), [15,16,[18], [19], [20], [21], [22]] were published in the first half of 2022. A similar proportion of studies were conducted in France (n = 4; 44%) [[15], [16], [17], [18]] and Germany (n = 3; 33%) [[19], [20], [21]]. Eight studies [[15], [16], [17], [18], [19], [20], [21], [22]] were retrospective single-arm cohort studies. The study with the largest number of participants (n = 1452) was conducted in Germany. Here, 250 KTRs were injected with a fourth dose of the vaccine, while sustained non-responders received up to five doses of the COVID-19 vaccine [19]. The duration between the third and fourth vaccination doses ranged from 28 to 126 days. We were unable to obtain the baseline information other than the primary outcome indicators in one study [17]. In the following statistical analyses, we collected the basic information for that study with the mean values of all other studies.

4.3. Patient characteristics

A total of 727 KTRs were included in this meta-analysis, all receiving a fourth dose of the SARS-CoV-2 vaccine. In eight studies, 42–70% of the patients were male, and the median age ranged from 53 to 64 years. All studies reported information on seroconversion following the fourth dose of the COVID-19 vaccine as the primary outcome. The median time from transplant to the fourth vaccine was between 5.5 and 9.9 years. One study analyzed the influence of different dose adjustment regimens of mycophenolic acid (MPA) on the serological response to the fourth vaccination [19].

4.4. Primary and secondary outcomes

Antibody responses after the fourth SARS-CoV-2 vaccine dose occurred in 42.9–88.1% of patients across the included studies. In the meta-analysis of nine studies with 727 KTRs, the pooled antibody response rate following the fourth vaccine was 60% (95% CI, 49–71%; I ² = 87.83%) (Fig. 2 ). We also performed a meta-analysis to determine the seroconversion rates between the third and fourth vaccine doses. The pooled proportion of KTRs seronegative after the third dose that transitioned to seropositivity after the fourth dose was 30% (95% CI, 15–48%; I ² = 94.98%, p < 0.01) (Fig. 2).

Fig. 2.

A. Pooled antibody response rate following the fourth vaccine; B. Seroconversion rates between the third and fourth.

4.5. Heterogeneity and sensitivity analyses

After excluding one study at a time from the analysis, we found that the fourth vaccine dose had an overall effectiveness rate of 56%, which did not change significantly. Heterogeneity was reduced to 56% after excluding the study conducted by Benotmane et al. [15]. We carefully analyzed the studies and hypothesized that the source of heterogeneity might be related to the technique of measuring serum antibodies, the rate of antibody positivity, the definition of serum antibody positivity, and other factors.

Sensitivity analysis was conducted using the leave-one-out random-effects DerSimonian-Laird model on the antibody response rate after the fourth vaccine. The result was consistent with that of the primary analysis, with a pooled seroconversion rate of 62% (95% CI, 50–73%) (Supplementary Fig. S1).

4.6. Safety

Seven studies reported the safety of the fourth vaccine dose. In all studies, neither major adverse events nor graft rejection were observed after the fourth vaccination (Table 2). In one study, one KTR presented with a recurrence of IgA nephropathy [17]. Another study reported that one patient who lacked neutralizing antibody activity after the fourth vaccine dose (ID₅₀ titer <7.5) developed symptomatic COVID-19 caused by the delta variant 19 days after receiving the fourth vaccination [15].

4.7. Subgroup analysis

We performed a subgroup analysis to examine the total number of participants, the percentage of seronegative patients before receiving the fourth vaccine dose, the time from the third to fourth vaccine dose, the name of the fourth vaccine, and the technique used to measure the primary outcome. There was no significant difference in the seropositivity rate when analyzing the total number of participants (54%; 95% CI, 45–63%; vs. 67%; 95% CI, 60–75%; vs. 59%; 95% CI, 54–64%; the heterogeneity between these subgroups had an I ² = 6.13% and p = 0.05; Fig. 3 ), name of the fourth vaccine (45%; 95% CI, 23–67%; vs. 76%; 95% CI, 51–100%; vs. 56%; 95% CI, 49–62%; vs. 58%; 95% CI, 38–79%; vs. 57%; 95% CI, 20–94%; vs. 50%; 95% CI, 40–60%; test of group differences: Q = 4.63, p > 0.05; Fig. 4 ), time from 3rd to 4th vaccine dose (55%; 95% CI, 37–74%; vs. 63%; 95% CI, 43–82%; vs. 63%; 95% CI, 56–70%; test of group differences: Q = 0.63, p > 0.05; Fig. 5 ), and primary outcome measurement technique used (88%; 95% CI, 80–96%; vs. 62%; 95% CI, 49–75%; vs.53%; 95% CI, 41–65%; vs.45%; 95% CI, 23–67%; vs. 57%; 95% CI, 20–94%, test of group differences: Q = 34.43, p < 0.05; Fig. 6 ). Our comparative analysis showed differences in sensitivity between the primary outcome measurement techniques used.

Fig. 3.

A. Subgroup analysis to examine the total number of participants; B. Subgroup analysis to the percentage of.

Fig. 4.

Subgroup analysis to the name of the fourth vaccine.

Fig. 5.

Subgroup analysis to the time from the third to fourth vaccine dose.

Fig. 6.

Subgroup analysis to the technique used to measure the primary outcome.

Serological tests currently available on the market showed striking differences regarding sensitivity. This study was the first that provided a side-by-side validation of four commercially available serological platforms (Euroimmun, Snibe/Medac, Roche, and Abbott) for detecting anti-SARS-CoV-2 antibodies. The results showed the highest sensitivities for the Euroimmun and Roche platforms. The seropositivity rate was the lowest in KTRs with a negative rate (before the fourth dose) in the 75–100% subgroup (54%; 95% CI, 48–59%), while it was the highest in those with a negative rate in the 0–25% subgroup (68%; 95% CI, 60–75%). The heterogeneity between these subgroups had an I ² = 10.18% (p = 0.0061; Fig. 3). As the proportion of negative patients before the fourth dose increased, the seroprevalence of patients receiving the fourth dose of vaccine decreased.

4.8. Publication bias

Publication bias was assessed using funnel plots (Supplementary Fig. S2). A Galbraith plot was used to assess the heterogeneity between the included studies (Supplementary Fig. S3).

4.9. Quality of evidence and risk of bias assessments

The results of the risk of bias assessment (Supplementary Table S2) and the quality of evidence of the nine included papers are summarized (Supplementary Table S3). Using the GRADE criteria, the quality of evidence was “low” in two studies [16,17] and “moderate” in seven studies [14,15,[18], [19], [20], [21], [22]]. According to the ROBINS-I tool, the risk of bias was “moderate” in eight studies [[14], [15], [16],[18], [19], [20], [21], [22]] and “serious” in one study [17].

5. Discussion

A study that included 136 renal transplant patients examined the humoral response to the BNT162b2 SARS-CoV-2 vaccine in renal transplant patients and showed that only 51 of the 136 transplant recipients (37.5%) tested serologically positive, much lower than the positivity rate in the control group (100%) [12]. KTRs have a high risk of neocrown infection despite vaccination. However, renal transplant patients did not obtain optimal seropositive protection from the third dose of the vaccine, making consideration of the fourth dose essential for this population. Studies on renal transplant patients receiving a fourth dose of the COVID-19 vaccine have been conducted in Germany, France, Norway, and other countries. As studies continue to accumulate on the potential benefits of a fourth COVID-19 vaccine dose in immunocompromised organ transplant patients, the World Health Organization has indicated that short-term benefits may be observed in immunocompromised individuals after a second booster [28].

This meta-analysis showed an improved immunogenic response to the fourth dose of the COVID-19 vaccine in KTRs. However, this improved immunogenic response is still unsatisfactory compared to the general population. One study evaluated the efficacy of a fourth dose of a COVID-19 mRNA vaccine against Omicron, reporting that mRNA vaccines induced the production of IgGs against the receptor-binding domain of SARS-CoV-2 and increased neutralizing antibody titers 9–10-fold after the fourth injection [29]. No serious or life-threatening adverse events were reported in transplant recipients who received a fourth dose of the vaccine.

Nine studies were included in the present review. In a large retrospective study of 250 KTRs from Germany that evaluated the serological response to 603 third, 250 fourth, and 40 fifth vaccinations against SARS-CoV-2 in renal transplant patients, the serological response rate increased to 29.4%, 55.6%, and 57.5%, respectively. Correspondingly, the cumulative serological response increased from 19.1% after two vaccinations to 42.0% after three, 74.2% after four, and 88.7% after five vaccinations [13]. Other studies of seronegative or hyporeactive patients after receiving the third dose confirmed an increased seropositivity rate after receiving a fourth dose of the new crown vaccine. An encouraging study conducted by Benotmane et al. in France reported a seropositivity rate of 88.1% after receiving the fourth dose. In this study <7.1 BAU/ml was considered negative, whereas <143 BAU/ml was considered a weak serological response. In this study, 87% of the participants (58/67) showed a weak antibody response after three doses, most likely contributing to the high seropositivity rate.

Factors associated with a reduced response after the fourth COVID-19 vaccine included degree of lymphopenia, longer time between the third and fourth doses, use of the BNT162b vaccine, antibody level and renal function at the time of vaccination, treatment with a low dose of steroids, treatment with belatacept, and MPA dose [[18], [19], [20], [21], [22]]. Five of the included studies evaluated neutralization capacity following the fourth vaccine dose [15,16,18,20,21]. One study reported that neutralizing antibodies against the Delta strain increased from 16% to 66% after the fourth dose. Roch et al. showed that functional SARS-CoV-2-reactive CD4 and CD8 T-cell responses were enhanced by 30–60% after the fourth COVID-19 vaccine dose [20]; another study found a cumulative serological response rate of 74.2% [19]. Thus, the antiviral response of renal transplant patients improved after the fourth vaccination.

The findings of the studies included in this review were consistent. All studies demonstrated a substantial benefit of the fourth dose of the COVID-19 vaccine in renal transplant recipients. The meta-analysis indicated a considerable proportion of seroconversion after the fourth vaccination.

The safety concerns evaluated in eight studies showed similar results. No serious adverse events or acute rejection episodes were observed after the fourth dose. In one study, one renal transplant patient presented with a recurrence of IgA nephropathy, four patients presented with fatigue and myalgia, and one patient had gastrointestinal symptoms [17]. In another study, one patient that lacked neutralizing antibody activity after the fourth injection (ID₅₀ titer <7.5) developed symptomatic COVID-19 caused by the Delta variant 19 days after receiving the fourth dose [15].

This study had several advantages. To the best of our knowledge, this study is the first to systematically evaluate the efficacy and safety of a fourth dose of COVID-19 vaccine in kidney transplant patients. These results clarify that kidney transplant patients can benefit from receiving a fourth dose of the COVID-19 vaccine. However, some limitations of our study are apparent. First, the included studies were observational, which resulted in a low quality of evidence. Second, the sample size was small. Third, there were differences in the methods used to measure serum antibody levels in individual studies. Finally, there is currently no standard for interpreting seropositivity rates, which may lead to variations in the reported seropositivity among studies. However, the stability of the results was verified using sensitivity and subgroup analyses, which we believe compensated for these deficiencies.

6. Conclusions

In kidney transplant patients, a fourth dose of the COVID-19 vaccine is associated with improved immunogenicity with no serious adverse effects. Nonetheless, a significant proportion of renal transplant patients remained seronegative even after receiving the fourth vaccine dose. This suggests that a fourth vaccination dose should be administered to kidney transplant patients in the absence of a good treatment plan for the new coronavirus epidemic. This may be an effective and safe option to protect this vulnerable group during the global epidemic of a novel coronavirus. However, these findings need to be verified and supplemented by additional clinical studies. Our recommendations are consistent with those of the World Health Organization [28].

Registration and protocol

The protocol was registered in PROSPERO, a prospective international registry of systematic reviews (CRD:42022334104). The review protocol can be accessed from the official PROSPERO website.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The authors declare no conflicts of interest.

Appendix A. Supplementary data

Supplementary material

Data availability

Data will be made available on request.