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1.
JCI Insight ; 7(9)2022 May 09.
Article in English | MEDLINE | ID: covidwho-1765224

ABSTRACT

Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression. Recent data from patients with autoimmune disorders suggest that temporary MPA hold might greatly improve booster vaccination outcomes. We applied a fourth dose of SARS-CoV-2 vaccine to 29 kidney transplant recipients during a temporary (5 weeks) MPA/azathioprine hold, who had not mounted a humoral immune response to previous vaccinations. Seroconversion until day 32 after vaccination was observed in 76% of patients, associated with acquisition of virus-neutralizing capacity. Interestingly, 21/25 (84%) calcineurin inhibitor-treated patients responded, but only 1/4 belatacept-treated patients responded. In line with humoral responses, counts and relative frequencies of spike receptor binding domain-specific (RBD-specific) B cells were markedly increased on day 7 after vaccination, with an increase in RBD-specific CD27++CD38+ plasmablasts. Whereas overall proportions of spike-reactive CD4+ T cells remained unaltered after the fourth dose, frequencies were positively correlated with specific IgG levels. Importantly, antigen-specific proliferating Ki67+ and in vivo-activated programmed cell death 1-positive T cells significantly increased after revaccination during MPA hold, whereas cytokine production and memory differentiation remained unaffected. In summary, antimetabolite hold augmented all arms of immunity during booster vaccination. These data suggest further studies of antimetabolite hold in kidney transplant recipients.


Subject(s)
Antimetabolites , COVID-19 Vaccines , COVID-19 , Kidney Transplantation , Antibodies, Viral , Antimetabolites/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immunity, Cellular , Immunity, Humoral , Immunosuppressive Agents/therapeutic use , SARS-CoV-2 , Transplant Recipients , Vaccination
2.
J Am Soc Nephrol ; 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1566580

ABSTRACT

Background: Accumulating evidence suggests that solid organ transplant recipients, as opposed to the general population, show strongly impaired responsiveness towards standard SARS-CoV-2 mRNA-based vaccination, demanding alternative strategies for protection of this vulnerable group. Methods: In line with recent recommendations, a third dose of either heterologous ChAdOx1 (AstraZeneca) or homologous BNT162b2 (BioNTech) was administered to 25 kidney transplant recipients (KTR) without humoral response after 2 doses of BNT162b2, followed by analysis of serological responses and vaccine-specific B- and T-cell immunity. Results: 9/25 (36%) KTR under standard immunosuppressive treatment seroconverted until day 27 after the third vaccination, while one patient developed severe COVID-19 infection immediately after vaccination. Cellular analysis seven days after the third dose showed significantly elevated frequencies of viral spike protein receptor binding domain specific B cells in humoral responders as compared to non-responders. Likewise, portions of spike-reactive CD4+ T helper cells were significantly elevated in seroconverting patients. Furthermore, overall frequencies of IL-2+, IL-4+ and polyfunctional CD4+ T cells significantly increased after the third dose, whereas memory/effector differentiation remained unaffected. Conclusions: Our data suggest that a fraction of transplant recipients benefits from triple vaccination, where seroconversion is associated with quantitative and qualitative changes of cellular immunity. At the same time, the study highlights that modified vaccination approaches for immunosuppressed patients still remain an urgent medical need.

3.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1311203

ABSTRACT

Novel mRNA-based vaccines have been proven to be powerful tools in combating the global pandemic caused by SARS-CoV-2, with BNT162b2 (trade name: Comirnaty) efficiently protecting individuals from COVID-19 across a broad age range. Still, it remains largely unknown how renal insufficiency and immunosuppressive medication affect development of vaccine-induced immunity. We therefore comprehensively analyzed humoral and cellular responses in kidney transplant recipients after the standard second vaccination dose. As opposed to all healthy vaccinees and the majority of hemodialysis patients, only 4 of 39 and 1 of 39 transplanted individuals showed IgA and IgG seroconversion at day 8 ± 1 after booster immunization, with minor changes until day 23 ± 5, respectively. Although most transplanted patients mounted spike-specific T helper cell responses, frequencies were significantly reduced compared with those in controls and dialysis patients and this was accompanied by a broad impairment in effector cytokine production, memory differentiation, and activation-related signatures. Spike-specific CD8+ T cell responses were less abundant than their CD4+ counterparts in healthy controls and hemodialysis patients and almost undetectable in transplant patients. Promotion of anti-HLA antibodies or acute rejection was not detected after vaccination. In summary, our data strongly suggest revised vaccination approaches in immunosuppressed patients, including individual immune monitoring for protection of this vulnerable group at risk of developing severe COVID-19.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/immunology , COVID-19/prevention & control , Kidney Transplantation/adverse effects , SARS-CoV-2 , Adult , Aged , Antibodies, Viral/biosynthesis , COVID-19 Vaccines/immunology , Case-Control Studies , Cohort Studies , Cytokines/immunology , Female , Humans , Immunity, Cellular , Immunity, Humoral , Immunization, Secondary , Immunoglobulin A/biosynthesis , Immunoglobulin G/biosynthesis , Immunologic Memory , Immunosuppressive Agents/adverse effects , Lymphocyte Activation , Male , Middle Aged , Monitoring, Immunologic , Renal Dialysis/adverse effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Transplantation Immunology
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