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Safety and Reactogenicity of 2 Doses of SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients

Ou, Michael T. BS1; Boyarsky, Brian J. MD1; Motter, Jennifer D. MHS1; Greenberg, Ross S. BS1; Teles, Aura T. BS1; Ruddy, Jake A. BS1; Krach, Michelle R. MS1; Jain, Vedant S. BA1; Werbel, William A. MD2; Avery, Robin K. MD2; Massie, Allan B. PhD1; Segev, Dorry L. MD, PhD1,3; Garonzik-Wang, Jacqueline M. MD, PhD1

Author Information
doi: 10.1097/TP.0000000000003780

Abstract

INTRODUCTION

Clinical trials of SARS-CoV-2 mRNA vaccines largely excluded immunosuppressed patients, such as solid organ transplant recipients (SOTRs).1,2 Although mRNA vaccines have been studied in preclinical and trial settings in healthy adults and those who have stable, chronical medical conditions, this novel vaccine platform has not been tested in SOTRs.3-5 Furthermore, limited knowledge about vaccine safety in this population may contribute to vaccine hesitancy; a recent survey of populations prioritized for early vaccination found that safety concerns were the most frequently cited reason for vaccine refusal.6 Although transplant society guidelines strongly recommend SARS-CoV-2 vaccination in transplant candidates and recipients,7 real-world safety data are necessary to inform patient and provider decision-making.

In our preliminary report of 187 SOTRs who received the initial dose of the BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) vaccine, participants reported minimal mild perivaccine reactogenicity; there were no reports of major safety events such as acute rejection, new neurological illnesses, or anaphylaxis.8 These findings were comparable to the reactogenicity observed in the original clinical trials in healthy adults and those with stable, chronic medical conditions.9,10 However, our initial cohort was limited to the initial vaccine dose and was too small to explore key risk factors. Additional safety profiles after completion of the entire vaccine series are needed, especially in light of higher proportion of adverse events seen in the original clinical trials after booster dosing.

To better understand the safety of SARS-CoV-2 mRNA vaccines in SOTRs, we studied recipients who completed the 2-dose vaccines series between December 9, 2020, and March 1, 2021. The goals of the study were to detail local and systemic reactogenicity and to determine the incidence of any major adverse events.

MATERIALS AND METHODS

Study Population

Participants were recruited through social media or their transplant centers between December 9, 2020 and March 1, 2021. English-speaking SOTRs ≥18 y old were eligible to participate. Age, sex, race, body mass index, prior COVID-19 diagnosis and hospitalization, transplant type and date, medications, other immune conditions, and allergies were collected and managed using Research Electronic Data Capture hosted at Johns Hopkins.11,12 Research Electronic Data Capture is a secure, web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture, (2) audit trails for tracking data manipulation and export procedures, (3) automated export procedures for seamless data downloads to common statistical packages, and (4) procedures for data integration and interoperability with external sources. As previously reported,13 blood samples were also collected after vaccination using either the TAPII blood collection device (Seventh Sense Biosystems) or standard venipuncture to determine antibody responses to vaccination. The study was approved by the Institutional Review Board at the Johns Hopkins School of Medicine and participants were consented electronically.

Reactogenicity After SARS-CoV-2 mRNA Vaccination

Questionnaires were distributed to participants 7 d after doses 1 and 2 (D1, D2). Only participants who completed both questionnaires were included. After each dose, participants were asked if they were newly diagnosed with COVID-19 and, if so, whether or not they required hospitalization, intensive care unit management, or mechanical ventilation. Local symptoms including pain, redness, and swelling, as well as systemic adverse reactions including fever, fatigue, headaches, chills, vomiting, diarrhea, and myalgias were captured using an ordinal scale of mild, moderate, or severe. Mild symptoms were defined as symptoms that did not interfere with daily activities, whereas moderate symptoms were defined as those that caused some interference with daily activity, and severe symptoms were defined as those that prevented daily activity.

Safety After SARS-CoV-2 mRNA Vaccination

Participants were asked to document any new infections requiring treatment, new diagnosis of acute rejection, onset of new neurological conditions such as Guillain-Barré syndrome or Bell’s palsy, or any cases of anaphylaxis requiring epinephrine. Participants were also invited to report any other medical illnesses, side effects, or symptoms.

Statistical Analysis

Local and systemic reactions after each dose were compared using a Wilcoxon signed-rank test for nonparametric, matched samples. We identified risk factors associated with any local or systemic symptom development, as well as the association between local and systemic symptoms and subsequent antibody development after mRNA dose 1 vaccination, using modified Poisson regression with robust error variance.14 Risk factors for symptom development included: age, sex, immunosuppression type, years since transplant, and vaccine manufacturer. As a sensitivity analysis, we redefined our outcome to those who developed moderate to severe symptoms. Missing data (≤5%) were handled using complete-case analysis and a 2-sided α = 0.05 was used. Analyses were performed using Stata 16.0/IC for Windows (College Station, TX).

RESULTS

Study Population Demographics and Clinical Characteristics

We studied 741 SOTRs who received BNT162b2 (54%) or mRNA-1273 (46%) vaccination (Table 1). Of the participants who completed the first questionnaire after D1, 91% also completed the questionnaire after D2. Median (interquartile range [IQR]) age was 60 (44–69); 57% were female, and 10% were non-White. Organs transplanted were kidney (49%), liver (19%), heart (15%), lung (11%), pancreas (1%), or multiple organs (5%), at a median (IQR) of 7 (3–14) y since transplant. Maintenance immunosuppression regimens included steroids (54%), calcineurin inhibitors (87%), antimetabolites (71%), and mammalian target of rapamycin (mTOR) inhibitors (13%). Fifteen SOTRs (2%) had been previously diagnosed with COVID-19 infection before being vaccinated.

TABLE 1. - Demographic and clinical characteristics of solid organ transplant recipients who completed an mRNA SARS-CoV-2 vaccine series
Participant characteristics TotalN = 741
Age, median (IQR) y 60 (44–69)
 Sex, % female 57
 Non-White, % 10
 Hispanic ethnicity, % 5
BMI, median kg/m2 (IQR) 25.8 (22.8–29.9)
Organ transplanted, %
 Kidney 49
 Liver 19
 Heart 15
 Lung 11
 Pancreas 1
 Multiorgan 5
Years since transplant, median (IQR) 7 (3–14)
Maintenance immunosuppression, % a
 Steroids 54
 Calcineurin inhibitors 87
 Antimetabolite 71
 mTOR inhibitors 13
 Other 3
 Prior SARS-CoV-2 infection, % 2
 Vaccine manufacturer, %
 BNT162b2 54
 mRNA-1273 46
aNot mutually exclusive.
BMI, body mass index; IQR, interquartile range; mTOR, mammalian target of rapamycin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Reactogenicity After Each SARS-CoV-2 mRNA Vaccine Dose

Pain at the injection site was the most commonly reported local reaction (84% after D1, 77% after D2), whereas the most common systemic symptoms were fatigue (36% after D1, 56% after D2) and headache (28% after D1, 42% after D2) (Figure 1). Aside from vomiting, all systemic adverse events were more frequent after D2. Severe symptoms were uncommon; the most common was fatigue (2% after D1, 3% after D2). Local site reactions were less common after D2 (85% versus 78%, P < 0.001) but systemic adverse events increased (49% versus 69%, P < 0.001) (Table S1, SDC, https://links.lww.com/TP/C207). Symptom frequency and severity did not significantly differ among the 15 patients with prior confirmed SARS-CoV-2 infection.

FIGURE 1.
FIGURE 1.:
Development of local and systemic adverse symptoms after each SARS-CoV-2 vaccine dose. D1, dose 1; D2, dose 2.

Risk Factors for the Development of Local and Systemic Reactogenicity

Females were more likely to experience systemic symptoms after either dose (adjusted incidence rate ratio [aIRR] = 1.111.311.55, P < 0.01 after D1, aIRR = 1.051.161.29, P < 0.01 after D2) (Table 2). Younger participants were also more likely to develop both local (aIRR per 10 y = 0.930.950.97, P < 0.001 after D1, aIRR per 10 y = 0.930.950.98, P < 0.001 after D2) and systemic (aIRR per 10 y = 0.850.900.94, P < 0.001 after D1, aIRR per 10 y = 0.910.940.97, P < 0.001 after D2) symptoms. Immunosuppression regimens including steroids were associated with a higher likelihood of developing local symptoms after dose 2 (aIRR = 1.021.111.20, P = 0.01). SOTRs who received the mRNA-1273 vaccine were more likely to develop local symptoms compared with the BNT162b2 vaccine (aIRR = 1.001.071.14, P = 0.03 after D1, aIRR = 1.081.161.25, P < 0.001 after D2).

TABLE 2. - Risk factors for the development of adverse symptoms following each SARS-CoV-2 vaccine dose
Dose 1 Dose 2
aIRR P aIRR P
Any local symptoms
 Sex, female 1.041.111.19 <0.01 0.981.071.16 0.13
 Age, per 10 y 0.930.950.97 <0.001 0.930.950.98 <0.001
 Years since transplant, per 5 y 0.991.001.02 0.6 1.001.021.05 0.07
 Immunosuppression regimen
  Includes antimetabolites 0.941.011.09 0.7 0.880.961.04 0.3
  Includes steroids 0.930.991.05 0.7 1.021.111.20 0.01
  Includes calcineurin inhibitors 0.890.991.11 0.9 0.891.021.17 0.8
  Includes mTOR inhibitors 0.951.051.15 0.3 0.971.091.22 0.2
 Vaccine manufacturer
  BNT162b2 Ref Ref
  mRNA-1273 1.001.071.14 0.03 1.081.161.25 <0.001
Any systemic symptoms
 Sex, female 1.111.311.55 <0.01 1.051.161.29 <0.01
 Age, per 10 y 0.850.900.94 <0.001 0.910.940.97 <0.001
 Years since transplant, per 5 y 0.951.001.05 >0.9 1.001.031.06 0.09
 Immunosuppression regimen
  Includes antimetabolites 0.720.85 1.00 0.06 0.830.921.02 0.11
  Includes steroids 0.850.991.15 0.9 0.890.981.08 0.7
  Includes calcineurin inhibitors 0.670.901.19 0.5 0.931.151.43 0.2
  Includes mTOR inhibitors 0.590.801.08 0.14 0.820.971.15 0.7
 Vaccine manufacturer
  BNT162b2 Ref Ref
  mRNA-1273 0.971.131.31 0.11 0.991.091.20 0.08
aIRR, adjusted incidence rate ratio; mTOR, mammalian target of rapamycin; Ref, reference; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

A sensitivity analysis showed that participants on maintenance immunosuppressive regiments that include steroids were more likely to develop moderate to severe local symptoms (aIRR = 1.021.341.77, P = 0.04 after D1, aIRR = 1.031.421.97, P = 0.03 after D2), and regiments that include mTOR inhibitors (sirolimus, everolimus) were more likely to develop moderate to severe local symptoms after dose 2 (aIRR = 1.031.582.42, P = 0.04). Participants who received the mRNA-1273 vaccine were also more likely to develop moderate to severe systemic symptoms (aIRR = 1.031.381.85, P = 0.03 after D1, aIRR = 1.111.411.79, P < 0.01 after D2). The effects of sex and age on symptom development were similar.

Risk Factors for the Development of Antibody Response After Dose 1

Participants who experienced moderate to severe pain (aIRR = 1.111.662.47, P = 0.01) or redness (aIRR = 1.833.928.41, P < 0.01) were more likely to develop an antibody response to dose 1 of mRNA vaccines (Table S2, SDC, https://links.lww.com/TP/C207).

Safety of SARS-CoV-2 mRNA Vaccines in SOTRs

There were no reported cases of anaphylaxis requiring epinephrine, onset of new neurological conditions such as Guillain-Barré syndrome or Bell’s palsy, or newly diagnosed COVID-19 infections. After D1, 23 SOTRs (3%) indicated that they acquired a new infection including upper respiratory infection, urinary tract infection, skin abscess, and pneumonia. After D2, 3 participants indicated a new infection including upper respiratory infection, urinary tract infection, and skin abscess. There was 1 case of acute rejection diagnosed after the second vaccine dose.

DISCUSSION

In this national study of 741 SOTRs who completed the full series of SARS-CoV-2 mRNA vaccines, we found that symptoms were consistent with vaccine reactogenicity demonstrated in original clinical trials in the general population9,10 and identified no major safety concerns. Systemic reactions were more common after the second dose and were associated with female sex and younger age, but severe reactions were rare overall (≤3%). Participants who experienced moderate to severe pain or redness were more likely to develop an antibody response to dose 1 of mRNA vaccines. These early findings may provide reassurance to transplant recipients and providers, helping guide decisions and address potential safety concerns.

Our findings parallel those reported in the original trials of the BNT162b2 and mRNA-1273 vaccines.9,10 Pain at the injection site, fatigue, and headache were the most common symptoms experienced by healthy adults and those with stable, chronic medical conditions, whereas older age was associated with decreased reactogenicity. Anaphylaxis was not documented in the published trial but has been reported after widespread distribution,15,16 and Bell’s palsy developed at a frequency similar to expected background rates.17 Our study found the same symptoms to be the most common in our population of 741 SOTRs, with no reports of anaphylaxis or other incident neurological conditions.

These findings may help address vaccine hesitancy and guide the decisions of patients and providers. A recent survey of populations prioritized for early vaccination found that >50% of respondents were either not likely or only somewhat likely to receive a vaccine.6 Concern about safety was the primary reason for hesitancy to vaccinate. As SARS-CoV-2 is expected to become endemic and likely to remain a persistent threat to the health of transplant recipients, vaccination may stem the spread of new viral variants that have been associated with increased mortality rates and transmissibility.18,19 Demonstrating the safety and efficacy of these mRNA vaccines in vulnerable populations is a necessary step forward toward mass vaccine acceptance and adherence.

We recently reported data on antibody generation after a single dose of mRNA vaccines in SOTRs.13 Recipients who did not receive antimetabolite maintenance immunosuppression, were younger, or who received the mRNA-1273 vaccine were more likely to develop antibodies. Interestingly, these same populations were also more likely to experience symptoms, especially those that were moderate to severe, as demonstrated in this article. Furthermore, we found that SOTRs who experienced moderate to severe pain and redness were 1.66-fold and 3.92-fold more likely to develop an antibody response. These results are not surprising; symptoms such as pain and redness may be indicative of the body’s recognition of foreign antigens and generation of an immune reaction. These side effects represent the physical manifestation of an inflammatory response.20 However, caution should be taken before interpreting the development of symptoms as proof of viral immunity or the lack of symptoms as warning of a failed immune response.

The strengths of this study include a national sample of SOTRs with early and novel information about adverse reactions after both doses of the BNT162b2 and mRNA-1273 vaccines. However, this study is limited by a smaller sample size than the large clinical trials, lacks non-SOTR controls, and does not offer long-term data about vaccine safety. Further information and long-term follow-up are needed before definitive safety profiles can be established. In addition, these were self-reported symptoms and conditions and may also be subject to response bias. Finally, there is a possibility that some patients who did not return their questionnaires may have experienced severe events that rendered them incapable of documenting such occurrences. It is also important to note that this was a nonrandomized, early, observational study leveraging a convenience sample of SOTRs with access to the vaccine, and as such, was not designed to evaluate vaccine efficacy.

In this prospective cohort, we found that adverse symptoms were consistent with expected vaccine reactogenicity and severe symptoms were rare. There were no major safety findings among our population that warrant immediate concern about SARS-CoV-2 mRNA vaccine safety in SOTRs. These early safety data may address vaccine hesitancy and refusal in transplant recipients and guide decision-making processes.

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