B and T Cell Responses after a Third Dose of SARS-CoV-2 Vaccine in Kidney Transplant Recipients.

BACKGROUND: Accumulating evidence sugges ts solid organ transplant recipients, as opposed to the general population, show strongly impaired responsiveness toward standard SARS-CoV-2 mRNA-based vaccination, demanding alternative strategies for protectio n o f 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 two doses of BNT162b2, followed by analysis of serological responses and vaccine-specific B- and T-cell immunity. RESULTS: Nine out of 25 (36%) KTR under standard immunosuppressive treatment seroconverted until day 27 after the third vaccination, whereas one patient developed severe COVID-19 infection immediately after vaccination. Cellular analysis 7 days after the third dose showed significantly elevated frequencies of viral spike-protein receptor-binding domain-specific B cells in humor al responders as compared with nonresponders. Likewise, portions of spike-reactive CD4 + T helper cells were significantly elevated in patients who were seroconverting. 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 a fraction of transplant recipients benefit 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 remain an urgent medical need. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/JASN/2021_11_23_briggsgriffin112321.mp3.

Impaired humoral immunity to SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients.

Patients with kidney failure are at increased risk for SARS-CoV-2 infection making effective vaccinations a critical need. It is not known how well mRNA vaccines induce B and plasma cell responses in dialysis patients (DP) or kidney transplant recipients (KTR) compared to healthy controls (HC). We studied humoral and B cell responses of 35 HC, 44 DP and 40 KTR. Markedly impaired anti-BNT162b2 responses were identified among KTR and DP compared to HC. In DP, the response was delayed (3-4 weeks after boost) and reduced with anti-S1 IgG and IgA positivity in 70.5% and 68.2%, respectively. In contrast, KTR did not develop IgG responses except one patient who had a prior unrecognized infection and developed anti-S1 IgG. The majority of antigen-specific B cells (RBD+) were identified in the plasmablast or post-switch memory B cell compartments in HC, whereas RBD+ B cells were enriched among pre-switch and naïve B cells from DP and KTR. The frequency and absolute number of antigen-specific circulating plasmablasts in the cohort correlated with the Ig response, a characteristic not reported for other vaccinations. In conclusion, these data indicated that immunosuppression resulted in impaired protective immunity after mRNA vaccination, including Ig induction with corresponding generation of plasmablasts and memory B cells. Thus, there is an urgent need to improve vaccination protocols in patients after kidney transplantation or on chronic dialysis.

Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients.

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.

Equation of state for partially ionized carbon and oxygen mixtures at high temperatures.

The equation of state (EOS) for partially ionized carbon, oxygen, and carbon-oxygen mixtures at temperatures 3×10(5)K is less than or approximately equal to T is less than or approximately equal to 3×10(6) K is calculated over a wide range of densities, using the method of free energy minimization in the framework of the chemical picture of plasmas. The free energy model is an improved extension of our model previously developed for pure carbon [Potekhin, Massacrier, and Chabrier, Phys. Rev. E 72, 046402 (2005)]. The internal partition functions of bound species are calculated by a self-consistent treatment of each ionization stage in the plasma environment taking into account pressure ionization. The long-range Coulomb interactions between ions and screening of the ions by free electrons are included using our previously published analytical model, recently improved, in particular for the case of mixtures. We also propose a simple but accurate method of calculation of the EOS of partially ionized binary mixtures based on detailed ionization balance calculations for pure substances.

Equation of state of classical Coulomb plasma mixtures.

We develop analytic approximations of thermodynamic functions of fully ionized nonideal electron-ion plasma mixtures. In the regime of strong Coulomb coupling, we use our previously developed analytic approximations for the free energy of one-component plasmas with rigid and polarizable electron background and apply the linear mixing rule (LMR). Other thermodynamic functions are obtained through analytic derivation of this free energy. In order to obtain an analytic approximation for the intermediate coupling and transition to the Debye-Hückel limit, we perform hypernetted-chain calculations of the free energy, internal energy, and pressure for mixtures of different ion species and introduce a correction to the LMR, which allows a smooth transition from strong to weak Coulomb coupling, in agreement with the numerical results.

Equation of state for partially ionized carbon at high temperatures.

Equation of state for partially ionized carbon at temperatures T approximately > or = 10(5) K is calculated in a wide range of densities, using the method of free energy minimization in the framework of the chemical picture of plasmas. The free energy model includes the internal partition functions of bound species. The latter are calculated by a self-consistent treatment of each ionization stage in the plasma environment taking into account pressure ionization. The long-range Coulomb interactions between ions and screening of the ions by free electrons are included using our previously published analytical model.

Electric microfield distributions in electron-ion plasmas.

The low-frequency electric microfield distribution in a Coulomb plasma is calculated for various plasma parameters, from weak to strong Coulomb coupling and from zero to strong electron screening. Two methods of numerical calculations are employed: the adjustable-parameter exponential approximation and the Monte Carlo simulation. The results are represented by analytic fitting formulas suitable for applications.