Comparison of the safety and immunogenicity of the BNT-162b2 vaccine and the ChAdOx1 vaccine for solid organ transplant recipients: a prospective study

Patients followed-up at the King Faisal Specialist Hospital and Research Centre who received two doses of either the BNT-162b2 vaccine or the ChAdOx1 vaccine were included in this study. Informed consent was obtained from all participants, and blood samples were obtained according to the follow-up schedule (Additional file 1: Appendix A).

The institutional ethics committee approved this study (RAC# 2211022). The key exclusion criterion for patients was known COVID-19 infection, multi-organ transplant and age < 18 years, receipt of the vaccine before transplant and history of rejection within 6 months preceding vaccine administration.

The primary outcome was the measurement of immunoglobulin G (IgG) antibodies against the RBD of the spike protein (anti-RBD) two weeks after first and second doses (Additional file 1: Appendix A). The two-week time point was selected based on previous studies that indicated that antibody titers are expected to peak at those time points [11‐13]. The anti-RBD was measured by semi-quantitative anti-spike serologic testing using the Roche Elecsys anti-SARS-CoV-2 spike enzyme immunoassay [14, 15]. Testing was performed according to the manufacturer’s instructions at a certified biochemistry testing hospital laboratory. The lower limit of detection of the assay was 0.4 U/mL; according to the test instructions, any level > 0.8 U/mL was considered positive. For the purposes of this study, we regarded any subject at or below 0.8 as negative. According to the manufacturer’s specifications, neutralizing antibodies were assessed via the SARS-CoV-2 surrogate virus neutralization test assay (GenScript). Horseradish peroxidase-conjugated spike RBD was incubated with serum and then moved to angiotensin-converting enzyme 2-coated wells. Interactions of RBD and angiotensin-converting enzyme 2 were blocked if neutralizing antibodies [16]were present in the serum. The surrogate virus neutralization test measures the total quantity of neutralizing antibodies in the sera [17]. A positive result was defined based on a neutralizing antibody limit of ≥ 30% neutralization/inhibition. At this limit, the negative and positive percent agreement with the conventional plaque reduction neutralization test 50 and plaque reduction neutralization test 90 assays was approximately 100%. The sensitivity and specificity of these assays were 93.80% and 99.4%, respectively, according to the manufacturer’s instructions. According to the kit specifications, individuals with neutralization less than 30% were considered negative for neutralizing antibodies.

Our secondary endpoints were solicited specific local or systemic adverse events within 7 days after the receipt of each dose of the vaccine, and unsolicited adverse events within 30 days after the receipt of the second dose of the vaccine (Additional file 11: Appendix A).

The study team members contacted all participants within 1 week of the receipt of each dose by phone to collect any adverse events. The data were collected at each scheduled visit (Additional file 1: Appendix A) to assess episodes of acute allograft rejection, hospitalization, other adverse events, or COVID-19 infection during the entire duration of the study.

The immunogenicity analysis was performed two weeks after the receipt of the first dose and 2 weeks after the receipt of the second dose for patients who received both vaccine doses and returned for follow-up. A safety analysis was performed for all patients, regardless of the number of doses administered. Demographic and safety analyses were performed using descriptive statistics. The primary outcome was vaccine immunogenicity assessed according to the anti-RBD titer two weeks after each dose of the vaccine, and will be further adjusted using propensity score analysis. A positive anti-RBD response was defined as > 0.8 U/mL. Univariate analyses were performed to determine factors impacting the development of a positive anti-RBD titer using the χ² or Fisher’s exact test for categorical variables and we analyzed for changes in the lab parameters between screening and before the 2nd dose, and between screening and after the 2nd dose via t-tests. Statistical significance was defined as p < 0.05. All statistical analyses were performed using Stata version 17.0 (College Station, TX, USA).

The primary immunogenicity endpoint was considered the most important factor determining the necessary number of participants for this study. Furthermore, the endpoint was assumed to be binary for sample size calculations; that is, the recruited participant either did or did not achieve a sufficient antibody titer level 2 weeks after the second dose.

Multivariable logistic regression analyses were performed to simultaneously investigate the relationship between subgroups and the rate of immunogenicity. Similar analyses were performed to determine the efficacy outcomes (i.e., infection).

Our cohort included 431 participants. Of these, 283 received the BNT-162b2 vaccine and 148 patients received the ChAdOx1 vaccine (230 kidney transplant recipients and 201 liver transplant recipients). The median age was 51.3 (± 16.2) years and 295 (68.4) were male. None reported a known history of COVID-19 prior to vaccination. All patient had stable graft function at the time of the vaccine. The baseline characteristics of the patients are described in Table 1. No significant differences in baseline characteristics were noted except for age (p > 0.00001) (Table 1).

The primary immunosuppressive regimen in the majority of the cohort composed of tacrolimus, mycophenolate and prednisone 235 (54.5%). With 408 (94.6%) of the patients were on tacrolimus as the cornerstone immunosuppressant. The immunosuppression intensity had the same impact on the vaccine response rate according to the neutralizing antibody (Table 1).

All patients were screened for COVID-19 before enrollment. Baseline laboratory test results and graft function were also assessed. There was no difference between patient’s laboratory parameters from baseline and two weeks following each dose of the vaccine (Table 2).

Factors previously reported to have affected seroresponse such as younger age, gender and time from transplantation were not clearly associated with response in our cohort. However, diabetes and triple immunosuppressive therapy appears to have significantly affected the response (Table 3).

A multivariable logistic regression was used including the same factors and demonstrated a pseudo R-square value of 0.23. Triple immunosuppressive therapy and age were identified as significant contributors for lack of response to the vaccine after the second dose with those receiving triple therapy having 92% reduced odds of a response and the per unit (year) increase in age associated with a 5% reduction in the odds of a response (Table 4).

In our cohort, the response rate after the first vaccine dose appeared to be higher with Pfizer vaccine (P < 0.0001). However, this elevation did not persist until after the second dose (P = 0.863) (Table 5).

However, type of organ transplant significantly affected the response rate in our cohort (p = 0.002) (Table 6).

The median antibody level before the second dose was 0.4 and after the second dose was 82.2. The median change in antibodies from before the second dose to after the second dose was 10.1

A total of 45 cases of COVID-19 were confirmed by polymerase chain reaction in this cohort; these cases occurred in 19 of 148 participants who received the AstraZeneca vaccine and in 26 of the 283 participants who received the Pfizer-BioNTech vaccine. P = 0.213 (Fig. 1; Table 7).

No evidence of graft dysfunction or rejection, or any other form of abnormality was observed in the entire cohort as evident by routine laboratory monitoring (Table 2). There were no significant changes in liver enzymes or liver function test results in the liver transplant population throughout the study period. There were no changes in serum creatinine levels in the kidney transplant population that necessitated any kidney allograft biopsy or further investigation. All side effects that occurred were grade 1 (mild) [18, 19], no medical intervention/therapy required. in this study were consistent with what’s been reported previously. Pain at injection site and fatigue occurred mainly with ChAdOx1 vaccine (Table 8).