LettersSeptember 2021

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

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    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 Transplanted

    Table 1

    We 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 & Johnson/Janssen), 9 received the mRNA-1273 vaccine (Moderna), and 6 received the 162b2 vaccine (Pfizer/BioNTech).

    We repeated antibody testing a median of 14 days (IQR, 14 to 17 days) after the third dose of vaccine. Of the 6 patients with low-positive antibody titers before the third dose, all had high-positive antibody titers after the third dose. In contrast, of the 24 patients with negative antibody titers before the third dose, only 6 (25%) had high-positive antibody titers after the third dose. Two (8%) had low-positive antibody titers, and 16 (67%) remained negative.

    Twenty-three patients completed a questionnaire 7 days after receiving their third dose that asked about specific vaccine reactions (Table 2). Fifteen patients reported mild or moderate local reactions, and 1 reported severe arm pain. The most frequent systemic reaction was mild or moderate fatigue in 14 participants; 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 Vaccine

    Table 2

    Discussion: 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).

    References

    • 1. Jackson LA Anderson EJ Rouphael NG et almRNA-1273 Study GroupAn mRNA vaccine against SARS-CoV-2—preliminary report. N Engl J Med2020;383:1920-31. [PMID: 32663912] doi:10.1056/NEJMoa2022483 CrossrefMedlineGoogle Scholar
    • 2. Boyarsky BJ Werbel WA Avery RK et alAntibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA2021;325:2204-6. [PMID: 33950155] doi:10.1001/jama.2021.7489 CrossrefMedlineGoogle Scholar
    • 3. Ali NM Alnazari N Mehta SA et alDevelopment of COVID-19 infection in transplant recipients after SARS-CoV-2 vaccination. Transplantation2021. [PMID: 34049360] doi:10.1097/TP.0000000000003836 CrossrefMedlineGoogle Scholar
    • 4. Danziger-Isakov L Kumar D AST ID Community of PracticeVaccination of solid organ transplant candidates and recipients: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant2019;33:e13563. [PMID: 31002409] doi:10.1111/ctr.13563 CrossrefMedlineGoogle Scholar

    Comments

    Lauren Palo, MHA, BSN, RN, PMP16 July 2021
    Vaccine Supply

    Thank you so much for your work and sharing your findings via this paper. We are submitting for IRB approval to conduct a study in our immunosuppressed solid organ transplant and oncology patients and were wondering if you would share insight as to how you obtained vaccine and/or the process you followed to obtain approval for use of existing supply of vaccine? 

    Dorry Segev, William Werbel7 July 2021
    Authors' Response to Dr. Rubin

    Critical research during a pandemic requires particular care in recruitment, methods, and participation, and we have been very fortunate to work with the Johns Hopkins Institutional Review Board to provide guidance in this space (COVID-19 Antibody Testing of Recipients of Solid Organ Transplants and Patients with Chronic Diseases; IRB00248540).

    Our prospective, national, real-world, ongoing observational vaccine study has enrolled >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 discussed, and formal recommendations in certain countries to utilize third doses as standard-of-care (for example, April 6 in France). Thus, it seems doubtful that our periodic communication with research participants is a primary driver of such practices in the US or abroad.

    Reporting vaccine immunogenicity and reactogenicity data as they emerge in the real world, with appropriate caveats regarding the nature of observational data, is the collective responsibility of the scientific community, especially given the ongoing COVID-19 pandemic worldwide, the specter of novel variants of concern, and the likelihood that this disease will remain an ongoing threat to immunocompromised patients unless vaccine protection is achieved.

     

    Eve Todesco, Alessandra Mazzola, Sarah Drouin, Fanny Hazan, Anne-Geneviève Marcelin27 June 2021
    Poor Efficiency of an Extra SARS-CoV-2 Vaccine Dose on Antibody Response in Solid Organ Transplant Recipients

    To the Editor,

    We read with interest the paper written by Werbel et al. reporting a poor anti-spike antibody response after a third dose of COVID-19 vaccine in solid organ transplant recipients (SOTR) with negative antibody titers after two doses (1). Actually, antibody response rate after two injections was dramatically low among SOTR in several recently published studies (2–5), highlighting a need of vaccinal strategy adaptation in this population.

    Here we would like to add data on humoral response after a third dose of BNT162b2 (Pfizer/BioNTech).

    Indeed, 74 SOTR vaccinated from January 2021 to June 2021 (Pitié-Salpêtrière hospital, Paris, France) with negative antibody titers after two doses (28 days apart) of BNT162b2 were retrospectively and consecutively included in the study (“Bureau de Protection des Données-APHP” registration number: 20210329192434). IgG to nucleocapsid and spike receptor binding domain were assessed at baseline and one month after each injection (Alinity i, Abbott Diagnostics, North Chicago, IL, USA).

    Median patient age was 63 years (IQR:54-68), and 78.4% (n=58) were male. Forty-five-point-nine percent were heart (n=34), 35.1% kidney (n=26) and 18.9% liver (n=14) transplant-recipients. Median time from transplantation to first BNT162b2 injection was 51.2 months (IQR:22.4-116.5). Calcineurin inhibitors-based immunosuppressive regimen was used in 87.3%, mycophenolic acid in 88.7%, steroids in 83.1% and mTor-inhibitor in 14.1% of the cases. Cardiovascular complications and diabetes were the most common comorbidities, with a frequency of 44.4% and 41.7% respectively. We observed a low seroconversion rate of 31.1% a median of 32 days (IQR:30-36) after the third dose: 42.9% (6/14), 19.2% (5/26) and 35.3% (12/34) in liver, kidney and heart recipients, respectively. Among responders, median titers of anti-spike IgG were of 366 AU/mL. None of the patients developed anti-nucleocapsid antibodies or reported Covid-19 symptoms. A time from transplantation to first injection < 2 years [OR 7.19; 95%CI (1.17-44.28); p= 0.033] and mycophenolic acid-based regimen [OR 9.73; 95%CI (1.61-58.68); p= 0.013] were the independent risk factors for negative anti-spike serology one month after the third injection.

    Altogether, 26.5% of the patients reported mild to moderate side effects.

    Our data increases the concern about mRNA vaccine immunogenicity in this population and suggests that SOTR could remain at high risk for COVID-19 disease even after three doses of BNT162b2. Vaccination of patient relatives could be a relevant option to protect them, alongside other safety measures.

     

    1. A.  Werbel W, J.  Boyarsky B, T.  Ou M, B.  Massie A, A.R.  Tobian A, M.  Garonzik-Wang J, et al. Safety and Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series. Annals of Internal Medicine [Internet]. 2021 Jun 15 [cited 2021 Jun 16]; Available from: https://www.acpjournals.org/doi/abs/10.7326/L21-0282
    2. Boyarsky BJ, Werbel WA, Avery RK, Tobian AAR, Massie AB, Segev DL, et al. Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients. JAMA. 2021 Jun 1;325(21):2204–6.
    3. Grupper A, Rabinowich L, Schwartz D, Schwartz IF, Ben-Yehoyada M, Shashar M, et al. Reduced humoral response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus. Am J Transplant. 2021 Apr 18;
    4. Rabinowich L, Grupper A, Baruch R, Ben-Yehoyada M, Halperin T, Turner D, et al. Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients. J Hepatol. 2021 Apr 20;
    5. Mazzola A, Todesco E, Drouin S, Hazan F, Marot S, Thabut D, et al. Poor Antibody Response after Two Doses of SARS-CoV-2 vaccine in Transplant Recipients. Clinical Infectious Diseases [Internet]. 2021 Jun 24 [cited 2021 Jun 25];(ciab580). Available from: https://doi.org/10.1093/cid/ciab580

     

    CORRESPONDING AUTHOR

    Eve Todesco, Sorbonne Université, INSERM, Institut Pierre Louis d’Epidémiologie et de Santé publique (iPLESP), AP-HP, Hôpital Pitié-Salpêtrière, Laboratoire de virologie, F-75013 Paris, France. Email: [email protected]. Fax: 33 1 42177411. Phone: 33 1 42177401.

    KEYWORDS

    SARS-CoV-2 vaccination; SOT-recipients; humoral response; COVID-19 disease; anti-spike antibodies; third dose.

    Acknowledgments

    We thank Filomena Conti, Benoît Barrou, Shaida Varnous and Dominique Thabut for following the patients and Cathia Soulié for collection of virological data.

    Funding

    None.

    Conflict of Interest

    None.

    Raymond A. Rubin, MD, FAASLD, AGAF, Bronwen H. Garner, MD, MPH21 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 < 1% of fully vaccinated transplant patients, including non-responders 2,3. We and others have launched prospective vaccination studies in solid organ transplant recipients assessing T and B-cell responses, cell-mediated immunity, safety, and the impact of additional boosters.

    Werbel et al detail a third vaccine’s impact on immunogenicity and reactogenicity in low/non-responder transplant recipients4. While the data are provocative, the methods raise important concerns. The authors state, “participants provided informed consent” implying written consent about the potential risks of another booster, such as the biopsy-proven rejection in one heart recipient. According to our patients who participated, they did not. After community-based standard dose vaccination, the original study1 participants received their antibody results and were invited to informational webinars. During these sessions and other communications, study staff addressed concerns that low/non-responders may remain vulnerable to COVID-19 and whether an additional booster with the same or another vaccine could stimulate seroconversion. They were told Johns Hopkins could not recommend treatment to “outside” patients, but they wanted their blood for another (this) study if they got another booster.  It appears that study staff underestimated their message’s compelling authority encouraging low/non-responders to seek out their own boosters. The evidence for this is that some of our patients (and likely from elsewhere) did so without consulting their transplant teams and by intentionally misleading their local vaccination sites about having already received the authorized two doses. In effect, a study-specific intervention (a booster) may have been induced without specific informed consent in an observational study without laboratory monitoring for post-booster complications. Moreover, participants got their third vaccinations when other non-study individuals were competing to secure their first shots, potentially escalating their infection risk.

    I am not questioning the investigators’ laudable intentions. Their initial observations1 quickly confirmed our expectations about reduced immunogenicity of COVID vaccines in solid organ transplant recipients. This current letter starts to address enhancing immunogenicity in low/non-responders, although it does not correlate reduced response with clinically meaningful outcomes or address the risk/benefit of modified dosing in this population. If taken to the extreme, the enthusiasm to answer other important, time-sensitive clinical questions with similar methods could lead to unintended and unmonitored serious consequences.

    1.  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 Jun 1;325(21):2204-2206. doi: 10.1001/jama.2021.7489.

    2. Tsapepas D, Paget K, Mohan S, Cohen DJ, Husain SA. Clinically Significant COVID-19 Following SARS-CoV-2 Vaccination in Kidney Transplant Recipients. Am J Kidney Dis. 2021 May 18;S0272-6386(21)00621-1. doi:10.1053/j.ajkd.2021.05.004. Online ahead of print.

    3. Wadei HM, Gonwa TA, Leoni JC, Shah SZ, Aslam N, Speicher LL. COVID-19 Infection in Solid Organ Transplant Recipients after SARS-CoV-2 Vaccination. Am J Transplant. 2021 Apr23. Doi10.1111/ajt.16618. Online ahead of print.

    Disclosures:

    RAR and BHG are research investigators in Moderna clinical trials.

    Dr SK Gupta14 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.