Safety and Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series

Letters15 June 2021Safety and Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case SeriesFREEWilliam A. Werbel, MD, Brian J. Boyarsky, MD, PhD, Michael T. Ou, BS, Allan B. Massie, PhD, Aaron A.R. Tobian, MD, PhD, Jacqueline M. Garonzik-Wang, MD, PhD, and Dorry L. Segev, MD, PhDWilliam A. Werbel, MDJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, Brian J. Boyarsky, MD, PhDJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, Michael T. Ou, BSJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, Allan B. Massie, PhDJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, Aaron A.R. Tobian, MD, PhDJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, Jacqueline M. Garonzik-Wang, MD, PhDJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this author, and Dorry L. Segev, MD, PhDJohns Hopkins University School of Medicine, Baltimore, MarylandSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L21-0282 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: The antibody response after 2 doses of an mRNA vaccine against SARS-CoV-2 is excellent in the general population (1), but the response is different in recipients of solid organ transplants. For example, we have found markedly attenuated antibody responses in transplant recipients after 2 doses of an mRNA vaccine against SARS-CoV-2 (2). In addition, reports of COVID-19 breakthrough infections in vaccinated transplant recipients (3) have prompted interest in administering additional doses of vaccine.Objective: To describe antibody responses and vaccine reactions in recipients of solid organ transplants who had a suboptimal response to standard vaccination and subsequently received a third dose of vaccine between 20 March 2021 and 10 May 2021.Case Series: This study was approved by the Johns Hopkins institutional review board, and participants provided informed consent.Thirty patients reported receiving a third dose of vaccine (Table 1). Their median age was 57 years (interquartile range IQR, 44 to 62 years), 17 were women, and 1 identified as non-White. None of the patients reported an illness before vaccination that was consistent with COVID-19 or a positive result on polymerase chain reaction (PCR) assay. In 25 patients, maintenance immunosuppression included tacrolimus or cyclosporine plus mycophenolate. In addition, corticosteroids were used for 24 patients, sirolimus for 1, and belatacept for 1. The median time between transplantation and initial vaccination was 4.5 years (IQR, 2.3 to 10.5 years). During the initial vaccination, 57% of the 30 patients received 2 doses of the 162b2 vaccine (Pfizer/BioNTech), and 43% received 2 doses of the mRNA-1273 vaccine (Moderna).Table 1 Vaccines Administered, Antibody Responses, Patient Characteristics, and Organs TransplantedWe tested all patients for antibodies against the spike protein at a median of 9 days (IQR, 2 to 33 days) before they received their third dose of vaccine; 24 patients had negative antibody titers, and 6 patients had low-positive antibody titers. Patients received the third dose of vaccine a median of 67 days (IQR, 54 to 81 days) after the second dose of their initial vaccine series; 15 patients received the Ad26.COV2.S vaccine (Johnson 1 patient reported severe headache, and 1 patient reported severe myalgia. No patient reported fever, and we did not observe any anaphylactoid reactions or neurologic complications. One heart transplant recipient had biopsy-proven, antibody-mediated rejection 7 days after her third dose of vaccine in the setting of acute volume overload. She did not experience an increase in her titer of antibodies against the spike protein, heart function remained normal, and immunosuppressive intensification was not initiated. In addition, no patient reported PCR-confirmed COVID-19 during additional follow-up, although the duration of this follow-up was limited.Table 2 Self-Reported Reactions After a Third Dose of VaccineDiscussion: To our knowledge, this is the first report of patients with solid organ transplants receiving a third dose of vaccine directed against SARS-CoV-2. It is encouraging that antibody titers increased after the third dose in one third of patients who had negative antibody titers and in all patients who had low-positive antibody titers. In addition, the vaccine reactions seem acceptable, given the benefits that these vaccines can confer. Antibody responses, however, appear to vary, and potential risks, such as organ rejection, should be evaluated on an individual basis.Limitations of this study include a small and heterogeneous convenience sample and the absence of assays for neutralizing antibody, B-cell memory, and T-cell responses.We believe that these observations support the use of clinical trials to determine whether booster doses to prevent COVID-19 in transplant patients can be incorporated into clinical practice, as they have been for hepatitis B and influenza vaccination (4).References1. Jackson LA, Anderson EJ, Rouphael NG, et al; mRNA-1273 Study Group. An mRNA vaccine against SARS-CoV-2—preliminary report. N Engl J Med. 2020;383:1920-31. PMID: 32663912 doi:10.1056/NEJMoa2022483 CrossrefMedlineGoogle Scholar2. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA. 2021;325:2204-6. PMID: 33950155 doi:10.1001/jama.2021.7489 CrossrefMedlineGoogle Scholar3. Ali NM, Alnazari N, Mehta SA, et al. Development of COVID-19 infection in transplant recipients after SARS-CoV-2 vaccination. Transplantation. 2021. PMID: 34049360 doi:10.1097/TP.0000000000003836 CrossrefMedlineGoogle Scholar4. Danziger-Isakov L, Kumar D; AST ID Community of Practice. Vaccination of solid organ transplant candidates and recipients: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33:e13563. PMID: 31002409 doi:10.1111/ctr.13563 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Dr SK GuptaClinical Assistant Professor Medicine , GS Medical College CCS Univ India14 June 2021 Third Dose of Covid vaccine, a Ray of Hope -for patients on Immunosuppressive therapy Encouraging results. Researchers tried to use various combination of vaccines as Prime and Boost. If the results can be extrapolated the study gives a ray of hope to patients with poor antibody response because of immunosuppressive treatment for various reasons. Deep analysis of data clear shows that a third dose booster based even on different like platform mRNA/Vector is neither better nor worse in augmenting the antibody response. This study is likely to wide implications world over where the vector based vaccines have in used in large numbers. Raymond A. Rubin, MD, FAASLD, AGAF, Bronwen H. Garner, MD, MPHRAR: Transplant Hepatology, Chief Scientific Officer, Piedmont Transplant Institute; BHG: Transplant Infectious Disease, Medical Director of Microbiology, Piedmont Healthcare21 June 2021 Timely topic, provocative results, but circumspection needed regarding the methods To the Editor: The Johns Hopkins team deserves praise for their innovative approach documenting the relatively low immunogenicity of the recommended doses of mRNA vaccines in solid organ transplant recipients1. While distressing, symptomatic COVID infections have been reported in 7000 persons in a 6-month period, leveraging digital recruitment, communications, and home-based self-administered blood draws to minimize risk to participants. All participants provide informed consent to undergo antibody testing using FDA emergency use authorized commercial platforms and to provide survey responses regarding vaccine reactogenicity and adverse events. The commentary by Drs. Rubin and Garner does not reflect the fact that, unlike in interventional trials, research participants in our observational registry undergo vaccination under their own accord, typically in concert with their medical providers, and thus consent regarding risks and benefits of vaccination itself are outside the bounds of our study. As part of the study design, we have been committed to sharing individual results of antibody testing with participants in real time. We provide an accompanying letter outlining the limitations of our current knowledge regarding significance of results and recommendation to discuss with their medical providers as to next steps, if any, while encouraging on multiple platforms the need to maintain protective behaviors regardless of antibody level. By popular demand, we have also conducted webinars to share aggregate published data, frame these results in clinical context, and answer questions about our ongoing research efforts. This has been another key forum to acknowledge and respect participants, whom we consider partners in the research effort, and provides an example of creative research communication in the pandemic climate where in-person site and coordinator visits carry potential major risks. Indeed, blunted antibody responses in transplant patients have been worrisome, particularly when paired with the much higher-than-expected rate of breakthrough infections. We applaud the multiple ongoing efforts of interventional trials such as additional vaccine doses or immunosuppression modulation under carefully controlled conditions. That said, we are aware of hundreds of transplant patients and other immunocompromised persons who have undergone third (and even fourth) booster vaccinations in the real world. Additionally, there have been high-profile national media reports of individuals who have received such additional vaccination, multiple social media groups where this approach is and in to third doses as example, 6 in it that our communication with research participants is a of such in the or vaccine immunogenicity and reactogenicity data as they in the real with regarding the of observational data, is the of the given the ongoing COVID-19 pandemic the of of and the that this disease remain an ongoing to immunocompromised patients vaccine is Transplant July 2021 Vaccine so much for work and sharing this We are for to a study in our solid organ transplant and patients and were if would share as to vaccine the to for use of of Article, and Disclosure William A. Werbel, Brian J. Boyarsky, MD, Michael T. Ou, Allan B. Massie, Aaron A.R. Tobian, MD, Jacqueline M. Garonzik-Wang, MD, Dorry L. Segev, MD, Johns Hopkins University School of Medicine, Baltimore, The are the of the authors and not reflect the or of the of and nor does of commercial or by the The authors thank the Johns Hopkins transplant vaccine study including T. A. and MD, They also thank H. MD, and for support and By the and from the of and and Kidney Diseases; from the of and Infectious Diseases; and from the Transplantation and of the American Society of Transplantation can be at Dorry L. Segev, MD, PhD, of Johns Hopkins Medical Baltimore, and William A. 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