Introduction
Individuals with COVID-19 who have undergone solid organ transplant (SOT) experience higher mortality and prolonged viral shedding compared with the general population.1,2,3,4,5 Multiple vaccine platforms have been proven successful in reducing viral spread and preventing poor outcomes in the general population.6,7,8 Unfortunately, recipients of SOT were excluded from the initial licensing trials of these vaccines, and accumulating data have shown reduced immunogenicity among recipients of SOT.9,10,11,12,13,14
The US Food and Drug Administration (FDA) has approved the COVID-19 mRNA vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) and has granted emergency use authorization (EUA) for the adenoviral vector vaccine Ad26.COV2.S (Janssen).15,16,17,18 In response to emerging SARS-CoV-2 variants and evidence of a mortality benefit from booster or additional doses, the US Centers for Disease Control and Prevention (CDC) recommended a booster or additional dose after completion of the primary COVID-19 vaccination series for all adults who received BNT162b2, mRNA-1273, or Ad26.COV2.S.19,20,21 For patients who are immunocompromised, including recipients of SOT, the CDC recommended an additional primary shot (third dose of mRNA COVID-19 vaccine for those receiving BNT162b2 or a booster dose of mRNA-1273) and a subsequent dose (fourth dose of BNT162b2 or second booster dose of mRNA-1273 for those receiving mRNA COVID-19 vaccine or second dose for those receiving Ad26.COV2.S).22 Despite this strategy, there are concerns for inadequate protection and risks of breakthrough infections among recipients of SOT because of diminished immunogenicity. We conducted this systematic review and meta-analysis to summarize the current evidence on vaccine responses and identify risk factors associated with diminished humoral immune response among recipients of SOT.
Methods
Data Sources and Searches
A systematic search was conducted independently by 2 of us (N.C. and K.M.) in MEDLINE, Embase, Web of Science (Clarivate), Cochrane Library, and ClinicalTrials.gov databases for research available through December 15, 2021. Complete search terms are included in the eMethods in the Supplement. Studies from different databases were combined, and duplicates were excluded. We did not limit our search by language. We conducted the study according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021277109).
Study Selection and Quality Assessment
Two authors (N.C. and K.M.) independently reviewed all studies and selected studies that reported the immunogenicity of COVID-19 vaccines in recipients of SOT, described as study participants in the methods and results. We included clinical trials and observational studies consisting of prospective cohort, retrospective cohort, and case-control studies. We excluded studies of humoral immunity after COVID-19 infection in study participants. Corresponding authors were contacted for immunogenicity testing or vaccination information if needed. We used Google Translate (Alphabet) to translate non-English studies during title and abstract screening. The Newcastle-Ottawa scale was used for assessing the risk of bias of the studies (eTable 1 in the Supplement).23 Conflicts were resolved by mutual consensus between reviewers.
Data Extraction
The checklist for critical appraisal and data extraction for systematic reviews of prediction modeling studies was used.24 Our primary outcome was the seroconversion rate after COVID-19 vaccine administration. We extracted the numbers of responders and total participants to calculate the seroconversion rates. Responders were defined as participants whose humoral response met definitions and cutoffs of antibody testing in each primary study. The numbers of responders, total participants, and odds ratios (ORs) with 95% CIs of factors associated with vaccine response were extracted. If ORs were not available, crude numbers were extracted for OR calculation.
Statistical Analysis
Descriptive statistics were used to characterize humoral immune response, the primary outcome, for each COVID-19 vaccine platform and for each number of doses. We then performed a meta-analysis with Comprehensive Meta-Analysis software version 3.3 (Biostat) to identify risk factors associated with poor humoral immune response. To determine the factors associated with humoral immunogenicity, pooled ORs (pORs) with 95% CIs for binary variables and differences in means (with SEs) for continuous variables were calculated using meta-analysis with the random-effects model. If the study provided both adjusted and unadjusted ORs, we used adjusted ORs for calculations. If the primary study provided ORs of the factors associated with vaccine nonresponse, we used log transformation to calculate ORs associated with vaccine response of those specific factors. We performed sensitivity analyses using a leave-1-out method.25 Funnel plot and Egger regression were used to assess the publication bias.26 If the P value of Egger regression was P < .1, the publication bias was considered significant.27 Factors with concerns of publication bias were further adjusted by the Duval and Tweedie trim-and-fill method.28 We assessed the heterogeneity of effect size estimates of each study using the I2 statistic. The I2 statistic ranged from 0% to 100%, with I2less than 25% indicating low heterogeneity; I2 of 25% to 60%, moderate heterogeneity; and I2 greater than 60%, substantial heterogeneity.29 P values were 2-sided, and statistical significance was set at P = .05. Data were analyzed from December 2021 to February 2022.
Results
Our initial search generated 2832 studies; 896 studies were removed because they were duplicates, and 1748 studies were excluded by screening through the titles and abstracts. We performed full-study reviews on 188 articles. After review, 105 articles were excluded owing to being a review article, case report, preprint, incorrect patient population, or duplicate cohort or having no outcomes of interest. A total of 83 studies9,10,11,12,13,14,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106 were included in the systematic review, of which 29 studies were included in the meta-analysis (Figure 1). The characteristics of 83 included studies are described in eTable 2 in the Supplement. There were 11 713 study participants across all studies, including heart, lung, heart-lung, liver, kidney, pancreas, kidney-pancreas, and other combined transplantation. Grading of recommendation assessment, development and evaluation for potential factors associated with seroconversion was reported in eTable 3 in the Supplement.107
Conclusions and Relevance
In this systematic review and meta-analysis, the rates of positive antibody response in solid organ transplant recipients remained low despite multiple doses of mRNA vaccines. These findings suggest that more efforts are needed to modulate the risk factors associated with reduced humoral responses and to study monoclonal antibody prophylaxis among recipients of SOT who are at high risk of diminished humoral response.
