Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case Series

LettersMarch 2022Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case SeriesFREESophie Caillard, MD, PhD, Olivier Thaunat, MD, PhD, Ilies Benotmane, MD, Christophe Masset, MD, Gilles Blancho, MD, PhDSophie Caillard, MD, PhDDepartment of Nephrology and Transplantation, University Hospitals of Strasbourg, INSERM Unit 1109, Strasbourg, FranceSearch for more papers by this author, Olivier Thaunat, MD, PhDDepartment of Transplantation Nephrology and Clinical Immunology, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, INSERM Unit 1111, Lyon, FranceSearch for more papers by this author, Ilies Benotmane, MDDepartment of Nephrology and Transplantation, University Hospitals of Strasbourg, INSERM Unit 1109, Strasbourg, FranceSearch for more papers by this author, Christophe Masset, MDInstitut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire de Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, Nantes Université, Nantes, FranceSearch for more papers by this author, Gilles Blancho, MD, PhDInstitut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire de Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, Nantes Université, Nantes, FranceSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L21-0598 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: Kidney transplant recipients receiving immunosuppressive drugs have impaired immune responses to messenger RNA (mRNA) COVID-19 vaccines (1). Consequently, despite standard vaccination with mRNA vaccines, many of these patients remain at high risk for severe disease during the ongoing pandemic. The U.S. Food and Drug Administration has authorized immunocompromised people to receive a third dose of mRNA vaccine after the standard 2-dose regimen to further boost protection, and French health authorities approved a third dose on 11 April 2021. Subsequent studies found that approximately 50% of patients who did not respond after a second dose seroconverted after a third dose, which produced an overall seroconversion rate of about 65% (2, 3). Antispike IgG titers above 143 binding antibody units (BAU) per milliliter correlate with the presence of neutralizing antibodies (the most widely accepted marker of disease protection) against the wild-type virus and the Alpha, Beta, and Gamma variants, but neutralization of the Delta variant requires higher antispike IgG titers (4). Therefore, patients with low titers of antispike IgG may remain insufficiently protected. In June 2021, French health authorities approved offering a fourth vaccine dose to recipients of solid organ transplants who had a weak response after a third dose.Objective: To investigate whether a fourth dose of an mRNA-based anti–SARS-CoV-2 vaccine would increase antispike IgG titers in kidney transplant recipients who showed a weak serologic response after 3 doses.Case Report: A fourth dose of mRNA vaccine (BNT162b2 [Pfizer], n = 34; mRNA-1273 [Moderna], n = 58) was given to 92 kidney transplant recipients from 3 independent French university hospitals (Strasbourg, Lyon, and Nantes) who had antispike IgG titers less than 143 BAU/mL 1 month after a third dose. All had measurements of antispike IgG titers 2 to 6 weeks later (median, 29 days [interquartile range, 26 to 34 days]). The Table shows the characteristics of these patients.Table. Characteristics of 92 Kidney Transplant Recipients Who Received a Fourth Dose of mRNA Vaccine Against SARS-CoV-2, According to Their Subsequent Levels of IgG Antibody Against the Spike ProteinThere were no safety concerns with the fourth vaccine dose. After a median of 29 days, median antispike IgG levels increased from 16.4 BAU/mL (interquartile range, 5.9 to 62.3 BAU/mL) to 145 BAU/mL (interquartile range, 27.6 to 243 BAU/mL) (Figure) and 50% of patients reached the threshold of 143 BAU/mL. Patients who reached this threshold had a longer interval between their transplant and fourth vaccine dose and were less frequently treated with steroids (Table). The percentage of patients who had antispike IgG titers above 143 BAU/mL after the fourth dose was 48% for the BNT162b2 vaccine and 52% for the mRNA-1273 vaccine, and patients who received the mRNA-1273 vaccine had higher IgG titers (median, 150 vs. 122 BAU/mL). Only 1 patient was subsequently diagnosed with mild COVID-19, and he had an antispike IgG level of 28 BAU/mL 1 month after his fourth vaccine dose.Figure. Antispike IgG titers measured 2–6 wk after the third and fourth vaccine doses in 92 kidney transplant recipients.Titers are expressed in BAU after calibration to the World Health Organization standard. The dotted line indicates the threshold of 143 BAU/mL. BAU = binding antibody units; D3 = third dose; D4 = fourth dose. Download figure Download PowerPoint Discussion: Our study indicates that a fourth dose of an mRNA-based vaccine produces a satisfactory antibody response in some kidney transplant recipients who did not respond adequately after 3 previous doses, and it supports the use of a fourth vaccine dose for these patients. We have shown in an unpublished study that kidney transplant recipients with previous COVID-19 had higher antispike IgG titers than uninfected recipients who were vaccinated. Assuming that the difference can be attributed to a higher antigen dose with infection than with vaccination, those results also support the use of additional, repeated doses of vaccine for kidney transplant recipients who do not respond adequately to standard vaccination. Prophylactic infusion of monoclonal anti–SARS-CoV-2 antibodies can be offered to patients who do not respond adequately to additional vaccine doses (5). For example, in our experience, only 10% of patients who did not respond (<1 BAU/mL) after the third dose were able to reach antispike IgG titers above 143 BAU/mL after a fourth dose. It would have been interesting to examine T-cell immunity after repeated vaccine doses in these patients, but the assays are time-consuming, which makes it challenging to implement them during routine practice. Finally, we recognize that an increase in antispike IgG titers does not invariably provide protection from infection and disease, which is why we encourage longitudinal studies with a sufficient duration of follow-up to evaluate the risk for COVID-19 in patients like these after additional vaccine doses.References1. 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;325:2204-2206. [PMID: 33950155] doi:10.1001/jama.2021.7489 CrossrefMedlineGoogle Scholar2. Benotmane I, Gautier G, Perrin P, et al. Antibody response after a third dose of the mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients with minimal serologic response to 2 doses. JAMA. 2021. [PMID: 34297036] doi:10.1001/jama.2021.12339 CrossrefMedlineGoogle Scholar3. Kamar N, Abravanel F, Marion O, et al. Three doses of an mRNA Covid-19 vaccine in solid-organ transplant recipients [Letter]. N Engl J Med. 2021;385:661-662. [PMID: 34161700] doi:10.1056/NEJMc2108861 CrossrefMedlineGoogle Scholar4. Planas D, Veyer D, Baidaliuk A, et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature. 2021;596:276-280. [PMID: 34237773] doi:10.1038/s41586-021-03777-9 CrossrefMedlineGoogle Scholar5. O’Brien MP, Forleo-Neto E, Musser BJ, et al; Covid-19 Phase 3 Prevention Trial Team. Subcutaneous REGEN-COV antibody combination to prevent Covid-19. N Engl J Med. 2021;385:1184-1195. [PMID: 34347950] doi:10.1056/NEJMoa2109682 CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Rujittika Mungmunpuntipantip; Viroj WiwanitkitPrivate Academic Contulant, Bangkok Thailand; Honorary professor, Dr DY Patil University, Pune, India12 January 2022 Correspondence on “Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients” Dear Editor, we would like to share ideas on the publication “. Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case Series. [1].” Caillard et al. concluded that “a fourth dose of an mRNA-based vaccine produces a satisfactory antibody response in some kidney transplant recipients who did not respond adequately after 3 previous doses, and it supports the use of a fourth vaccine dose for these patients. [1].” We agree that the fourth dose of the vaccine might be useful. However, as Cailard et al. already noted, there are many factors to be considered. The background immune status of different subjects might be different and the vaccine response is generally based on background immune status [2]. Whether an additional dose of vaccine will be useful for protection of kidney transplant recipient is still an issue for further studied. However, it might or might not directly tell us the utility of the additional dose vaccination. As Caillard et al. noted, the antibody level cannot directly imply protection. Additionally, an evaluation of antispike antibody titer after vaccination cannot also rule out the possibility of post vaccination silent COVID-19 infection. A long-term follow-up might give additional data. If we would like to study on utility, we should start from assessment of background immune status of the patient and specific laboratory investigation on both T-cell and B-cell function after vaccination should be performed. Conflict of interest: None References Caillard S, Thaunat O, Benotmane I, Masset C, Blancho G.Antibody Response to a Fourth Messenger RNA COVID-19 Vaccine Dose in Kidney Transplant Recipients: A Case Series. Ann Intern Med. 2022 Jan 11. doi: 10.7326/L21-0598. Online ahead of print. Duni A, Markopoulos GS, Mallioras I, Pappas H, Pappas E, Koutlas V, Tzalavra E, Baxevanos G, Priska S, Gartzonika K, Mitsis M, Dounousi E. The Humoral Immune Response to BNT162b2 Vaccine Is Associated With Circulating CD19+ B Lymphocytes and the Naive CD45RA to Memory CD45RO CD4+ T Helper Cells Ratio in Hemodialysis Patients and Kidney Transplant Recipients. Front Immunol. 2021 Dec 3;12:760249. Christine Weart MDRetired internist ( NY Presbyterian Hospital)24 January 2022 4th vaccine in kidney transplant patients This study was also done by Dr. Dorry Segev at Johns Hopkins and showed most with each successive Covid vaccine developed higher antibodies. I was in the study as I am treated with an early transplant drug for a rare leukemia with zero response to vaccines #1&2 (Pfizer), so opted for full dose (Moderna) next yielding minimal protection and then got maximal protection after second Moderna. Eternally grateful to these researchers! https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612849/ Author, Article, and Disclosure InformationAffiliations: Department of Nephrology and Transplantation, University Hospitals of Strasbourg, INSERM Unit 1109, Strasbourg, FranceDepartment of Transplantation Nephrology and Clinical Immunology, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, INSERM Unit 1111, Lyon, FranceInstitut de Transplantation Urologie Néphrologie, Centre Hospitalier Universitaire de Nantes, Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, Nantes Université, Nantes, FranceDisclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L21-0598.Corresponding Author: Sophie Caillard, MD, PhD, Department of Nephrology and Transplantation, Hôpitaux Universitaires de Strasbourg, 1, place de l’Hôpital, 67091 Strasbourg, France; e-mail, Sophie.[email protected]fr.This article was published at Annals.org on 11 January 2022. 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