key: cord-0948394-m2f7q37e
authors: Ali, Haris; Ngo, Dat; Aribi, Ahmed; Arslan, Shukaib; Dadwal, Sanjeet; Marcucci, Guido; Nakamura, Ryotaro; Forman, Stephen J.; Chen, Jason; Malki, Monzr M. Al
title: Safety and Tolerability of SARS-CoV-2 Emergency-Use Authorized Vaccines Allogeneic Hematopoietic Stem Cell Transplant Recipients.
date: 2021-07-15
journal: Transplant Cell Ther
DOI: 10.1016/j.jtct.2021.07.008
sha: bd962e478a7721a96844fa435bed55c8c9e72460
doc_id: 948394
cord_uid: m2f7q37e

BACKGROUND: : The safety and efficacy of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emergency-use authorized (EUA) vaccines has been confirmed in general population. However, there is no data on its safety/tolerability or efficacy in recipients of allogeneic hematopoietic stem cell transplant (HCT). OBJECTIVES: : We performed this study to identify the incidence of adverse events following SARS-CoV2 EUA vaccines and the incidence of new onset GVHD or worsening of existing GVHD after EUA vaccine administration and the incidence SAR-CoV2 positivity in vaccinated HCT patients. STUDY DESIGN: : We retrospectively reviewed 113 HCT patients who received at least one dose of EUA vaccine to describe the safety/tolerability, any impact on graft-versus-host disease (GVHD), and incidence of SARS-CoV2 PCR positivity after vaccination. Patients received either Pfizer (BNT162b2) or Moderna (mRNA-1273) vaccines. Patients were included if they were 18 years or older and received at least one dose of vaccine in the post HCT setting. RESULTS: : Most patients presented with myalgias/arthralgias (first dose 7.7%, second dose 14.6%), fatigue (first dose 15.4%, second dose 29.2%), and injection site pain (first dose 40.4%, second dose 43.8%). Other side effects experienced by patients included: nausea, vomiting, diarrhea, headache, injection-site rash and swelling. Liver function abnormalities occurred in 18.6% of patients. The incidence of neutropenia, thrombocytopenia, and lymphopenia occurred at 13.3%, 11.5%, and 8.8% respectively. Forty percent of patients who had active chronic GVHD at the time of vaccination where worsening chronic GVHD occurred in 3.5% of patients. New chronic GVHD developed in 9.7% of patients after vaccination. CONCLUSION: : In conclusion, the SARS-CoV2 EUA vaccines were well-tolerated in allogeneic HCT recipients.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) is a novel coronavirus emerging from Wuhan, China that can cause severe respiratory illness and a myriad of other complications that is now known as COVID-19. This disease was declared a pandemic by World Health Organization in March 2020 and has affected hundreds of millions of people worldwide [1].

COVID-19 clinical presentations can vary greatly between patients and those who are at highest risk for severe illness leading to hospitalization and/or death include older age, obesity, diabetes, and immunocompromised state, amongst other conditions [2] .

Since December 2020, three vaccines have been approved under an Emergency Use (mRNA-1273) had greater than 90% efficacy with a tolerable safety profile [3, 4, 5, 6, 7] . Among BNT162b2 recipients 26.7% reported adverse events compared to 12.2% placebo, which included local injection site reactions, pyrexia, fatigue, chills, myalgia/arthralgia, nausea and headaches [3, 4, 5, 8] . Similarly, mRNA-1273 had higher solicited adverse events compared to placebo with Grade 3/4 systemic adverse events occurring in 15.8% of recipients after the second dose of vaccine with manifestations like those reported with BNT162b2 [6, 7, 8] . These two EUA vaccines in registration clinical trials had very low rates of serious adverse effects.

Cancer is a risk factor for developing severe COVID-19, which can be attributed to immunosuppression from the underlying disease and/or therapeutic interventions for treating the cancer [9] . In particular, patients with hematologic malignancy and HCT recipients the mortality from COVID-19 is significantly higher than the general population [10, 11, 12] The risk of increased mortality can be due to the various factors such as type of hematologic malignancy, chemotherapy regimens used, neutropenia, lymphopenia, type of conditioning regimen used in preparation of HCT ongoing immunosuppressive medications for prevention of graft versus host disease (GVHD) or active treatment of GVHD after HCT. [13, 14] . None of the clinical trials of SARS-CoV2 EUA vaccines included immunocompromised patients, specifically HCT recipients [3, 4, 6, 7] . Prevention of COVID-19 in HCT recipients is the key intervention and requires a multi-faceted approach. The best intervention would be vaccinating healthy caregivers, but that was not a reality with a vaccine shortage during the pandemic. Furthermore, NCCN, ASTCT, and ASH recommended vaccinating allogeneic HCT patients with specific guidance relating to time from HCT and other factors. The decision making is complex when compared to the general population as the provider must balance the patient's higher risk for severe COVID-19 due to immunosuppressed state versus the likelihood of poor vaccine response [15, 16] . Currently, there is no information on the safety of EUA vaccines in HCT patients and the potential impact on GVHD.

Given the lack of safety and tolerability data in HCT population, we performed this study to identify the incidence of adverse events following SARS-CoV2 EUA vaccines. We also reviewed the incidence of new onset GVHD or worsening of existing GVHD after EUA vaccine administration and the incidence SAR-CoV2 positivity in vaccinated HCT patients.

This retrospective study was performed at City of Hope National Medical Center that collected data from electronic medical records to identify HCT patients who received at least a dose of SARS-CoV2 EUA vaccine between December 2020 and April 2021. Patients at our institution during the study period could only receive Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) mRNA vaccine. Inclusion criteria: patients who were 18 years or older and received at least one dose of vaccine in the post HCT setting. There were no exclusion criteria. Additional details about potential side effects following vaccination were gathered by a voluntary COVID-19 vaccine survey (see Figure 1 in Appendix) offered to patients by their physician that was registered into their medical record. Patients were required to have at least one physician followup assessment after a minimum of one week following the first dose of vaccine, in addition, only physician assessments within 40 days after receiving their last dose of vaccine were included in the analysis. The initial follow-up period was intended to be 30 days, but due to the retrospective nature of this study, it had to be extended to 40 days to ensure adequate capture of physician assessments following vaccination. This study was approved by an institutional review board.

The primary endpoint was the incidence of patient reported and clinical laboratory adverse events from the BNT162b2 or mRNA-1273, up to 40 days after the final vaccine dose. Patientreported adverse events required documentation by a physician of vaccine tolerability or a response to a voluntary COVID-19 survey from the patient to be considered evaluable. Incidence rate was reported based off the vaccination dose received by the patient. Severity of patientreported adverse events (e.g. fevers, myalgias) were unable to be graded by CTCAE version 5.0 due to a lack of details on severity in physician documentation to appropriately grade these adverse events, and as a result, patient-reported adverse events would only be reported as an incidence rate. Baseline laboratory parameters such as white blood cell count, absolute neutrophil count, absolute lymphocyte count, platelets, eosinophils, serum creatinine, and liver function tests were collected. Abnormalities in laboratory parameters following vaccination were documented and graded using the CTCAE version 5.0 for severity if newly developed abnormality or worsening of severity from baseline after vaccination where highest grade would be used for analysis. Grading for acute GVHD using the Mount Sinai Acute GVHD International Consortium (MAGIC) criteria or chronic GVHD using the NIH consensus criteria was not consistently available in physician documentation. Therefore, incidence of new or worsening of GVHD was determined based on documentation in the electronic medical record of an intervention for GVHD such as increasing dose of current GVHD medications not due to subtherapeutic levels or initiation of a medication to treat GVHD. The onset of new or worsening GVHD was required to have occurred within 40 days of the last vaccine dose received to be included in the study results. Clinical laboratory adverse event and GVHD incidences were reported as a cumulative rate. Incidence of positive SARS-CoV2 viral, symptomatic COVID-19 infection, and/or COVID-19 complications following vaccination were collected throughout the study period with frequency of testing based on institutional policies and physician discretion. A SARS-CoV2 test was deemed positive if a nasal swab, nasopharyngeal swab, or saliva tested positive for SARS-CoV-2 via nucleic acid amplification, or antigen test [17, 18] .

There were 113 patients who met inclusion criteria with baseline characteristics summarized in Table 1 . There were eight patients who did not have a documented second dose in the electronic medical record and as a result was only followed for 40 days after the first vaccine dose. Median 

Only 36 of the 113 patients (31.9%) responded to the survey to assess adverse effects after vaccination was completed. Median time to survey response from first dose of vaccine received was 35 days (range 2-108 days). In addition to these 36 patients, physician documentation of patient-reported adverse events occurred in 16 patients during their first dose and 12 patients during the second dose of vaccine, which resulted in 52 and 48 patients being evaluable respectively. As summarized in Table 2 , the major adverse events experienced by patients were myalgias, arthralgias, fatigue, and injection site pain. Due to varying physician practices and inconsistent frequency of laboratory monitoring, resolution times of toxicities may have been overestimated and are not presented here. Rates of myalgia and arthralgia from first dose and second dose of vaccine were reported to be 7.7% and 14.6% respectively. There was a difference in rate of fatigue between the first and second dose, with incidence of fatigue 13.8% higher after the second dose. Injection site pain after the first and second dose occurred at 40.4% and 43.82% respectively, which was much lower than reported with registration trial for BTN162b2 (71-83% for first dose and 66-78% and second depending on age) and mRNA-1273 (83.7% for first dose and 88.2% for second dose) [3, 4, 5, 6, 7] . Other side effects experienced by patients included:

nausea, vomiting, diarrhea, headache, injection-site rash and swelling. One patient had axillary lymphadenopathy on the arm of the injection site and another patient an increase in blood pressure and tachycardia shortly after receiving the vaccine.

Cumulative incidence of clinical laboratory adverse events for all patients who received at least one dose of vaccine is summarized in Table 3 . As mentioned previously, eight patients only received one dose of vaccine with no documented second dose in the electronic medical record.

Hepatic impairment was observed in 21 of 113 patients (18.6%) with a median of 26 days (range 3-66) to evaluation of adverse event. This was defined by an elevation in either bilirubin, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) after first vaccination. One patient with a baseline Grade 1 hepatic impairment who was recently started on an azole for antifungal prophylaxis experienced a Grade 4 increase in AST and Grade 3 increase ALT that occurred 26 days after his only dose of vaccine that returned to baseline approximately one week later after discontinuation of azole. Another patient experienced a Grade 3 increase in both the ALT and AST that occurred four days after the second dose of vaccine. This patient was initiated on prednisone and ruxolitinib for new onset GVHD of skin and mouth on evaluation and eventually liver toxicity resolved within a month. The incidence of neutropenia, thrombocytopenia, and lymphopenia occurred at 13.3%, 11.5%, and 8.8% respectively. Seven patients who experienced bone marrow suppression were actively being treated with chemotherapy at the time, where six patients were being treated for relapse and one was on maintenance post-HCT. There were five patients experienced eosinophilia while being vaccinated with one patient arriving to urgent care for treatment of pneumonia at time of eosinophilia.

Prior to the first dose of vaccine, baseline chronic GVHD was present in 39.8%, mostly with skin (68.9%) and oral (37.8%) involvement. Table 4 and myalgias (6.1-23.7%) based on the similar criteria as the BNT162b2 population [6, 7] . Both vaccines showed significantly worse adverse events reported after the second dose. Our safety results in the allogeneic transplant patient population are comparable to the safety results found in the clinical studies submitted to the FDA for emergency use authorization for both vaccines.

Unfortunately, our data did not include Ad26.COV2.S to make any conclusions on this vaccine's safety in this specific population. Only two patients tested positive for SARS-CoV2 by PCR after receiving the vaccine, which was believed to be due to viral shedding since these patients had a prior history of SARS-CoV2 infection were asymptomatic requiring no hospitalization. The adverse events reported in BNT162b2 and mRNA-1273 registration trials remained prominent in our study, with a caveat that it occurred at lower rates. This could be due to a low survey response rate and possibly recall bias from the patients who did complete the survey that was not in real-time, as patients tend to only report more severe adverse events to physicians unless in a clinical trial setting. Another potential explanation of lower incidence rates of adverse events could be an impaired immune response to the vaccine in the HCT population as significant proportion of vaccine recipients had active chronic GVHD The required uptake of mRNA from BNT162b2 or mRNA-1273 by dendritic cells to encode for the necessary spike protein and ability to mobilize adaptive immunity via T-cells and B-cell lymphocytes towards COVID-19 might be suboptimal in HCT patient, as immune function might not normalize until a year after HCT and might further be delayed by GVHD and its treatment [19, 20] .

Approximately 12% of patients in our study had worsening of baseline chronic GVHD or development of new-onset chronic GVHD after vaccination. Currently, there are very few studies evaluating the relationship between vaccines and incidence of GVHD. A study published by Natori, et al. reported an incidence of new or worsening GVHD in about approximately 26% of patients who received the influenza vaccine but did not have a comparator group [21] .

Baumrin, et al. analyzed the effect of the recombinant zoster vaccine on GVHD incidence and concluded no significant difference [22] . We also observed few cases of eosinophilia, and hepatic impairment that occurred after the vaccination, however, it is difficult to ascribe causality to the vaccines due to the retrospective nature of this study. Messenger RNA vaccines can be highly immunogenic and in the clinical trials younger population had a more robust immune response as suggested by higher rates of adverse events and the same biologic effect can be seen in our HCT patients. However, with ongoing immunosuppression and high incidence of chronic GVHD the rates of some adverse effects were less in our patients. Because of the high immunogenicity from the vaccines, activation of inflammatory pathways might lead to the cause of all the immune-related adverse events even in this immunocompromised patient population.

Our study had several limitations, it is retrospective in nature and had a small sample size. A low survey response rate due to its voluntary nature, recall bias, and the usage of physician documentation when survey responses were unavailable was also a limitation in getting a detailed description of patient solicited local and systemic adverse events. In addition, the smaller than expected sample size might have impacted patient reported outcomes that might have led to a lower solicited adverse event rate compared to published studies. Laboratory results were not collected at consistent time frames and the frequency of collection was driven by the patient's overall clinical management rather than routine monitoring relative to vaccination. With a median of only two physician assessments to evaluate for adverse events, this could have potentially affected the results regarding incidence of laboratory adverse events and the time to onset of clinical laboratory adverse event relative to vaccination. However, our results do provide some clarity on the safety and tolerability of mRNA EUA vaccines in HCT patients.

More comprehensive studies are needed on safety of SARS-CoV2 vaccines in HCT population especially from standpoint predicting risk of GVHD, whether new-onset or worsening of baseline GVHD with these novel vaccines using mRNA, as well as patient education on risks.

Furthermore, of importance is assessing immunogenicity of vaccines when given early after HCT or later, especially in the context of existing guidelines for vaccinating HCT patients including SARS-CoV2 in the setting of the pandemic [23, 24, 25] . Our study provides much needed preliminary data that both EUA mRNA vaccines were safe and well tolerated in an allogeneic HCT population despite some major limitations of our study.

Financial disclosure: Dat Ngo has served on an advisory board with Pfizer. There are no other potential conflicts of interest to disclose. 

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