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Randomized Controlled Trial
. 2024 Oct 8:15:1463769.
doi: 10.3389/fimmu.2024.1463769. eCollection 2024.

Role of SARS-CoV-2-specific memory B cells promoting immune protection after booster vaccination in solid organ transplantation

Laura Donadeu  1   2 , Susana Gomez-Olles  2   3   4 , Franc Casanova  1   2 , Alba Torija  1   2 , Manuel Lopez-Meseguer  2   3   4   5 , Meritxell Boada-Pérez  2   3 , Delphine Kervella  1   2   6 , Elena Crespo  1   2 , Claudia Carrera-Muñoz  1   2   6 , Isabel Campos-Varela  2   7   8 , Lluís Castells  2   7 , Maria F Cortese  9 , Juliana Esperalba  2   9 , Candela Fernández-Naval  9 , Jesús Quintero  2   10 , Marina Muñoz  2   11 , Fernando Agüero  12 , José Gonzalez-Costello  13 , Laura Lladó  14 , Alexandre Favà  15 , Laura Cañas  16 , María Del Mar de la Hoz-Caballero  17 , Maria Meneghini  1   2   6 , Irina B Torres  2   6 , Mariona Juvé  1 , Fmj Hafkamp  1   2 , Marta Vila  9 , Alba G Robles  18 , Maria José Buzón  18 , Nestor Toapanta  2   6 , José Miguel Zúñiga  1   2   6 , Víctor Monforte  2   3   5 , Berta Saez-Giménez  2   3   5 , Oscar Len  2   19 , Ibai Los Arcos  2   19 , Enric Miret  2   20 , Gema Ariceta  2   11 , Emma Pardo  6 , Xavier Martínez  21 , Francesc Moreso  2   6 , Oriol Bestard  1   2   6
Affiliations
Randomized Controlled Trial

Role of SARS-CoV-2-specific memory B cells promoting immune protection after booster vaccination in solid organ transplantation

Laura Donadeu et al. Front Immunol. .

Abstract

Introduction: Solid organ transplant (SOT) recipients display weak seroconversion and neutralizing antibody (NAb) responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and remain at risk of severe coronavirus disease 2019 (COVID-19). While B-cell memory is the hallmark of serological immunity, its role in driving successful vaccine responses and providing immune protection in SOT patients remains unclear.

Methods: We investigated the function and interplay of SARS-CoV-2-specific memory B cells (mBc), different cytokineproducing T cells, and cross-reactive NAb in driving seroconversion and protection against COVID-19 in two cohorts. First, we studied a large cohort of 148 SOT recipients and 32 immunocompetent individuals who underwent several vaccinations. Subsequently, we assessed 25 SOT patients participating in a randomized controlled trial to compare two different immunosuppressive strategies for allowing successful seroconversion and memory-cell responses after booster vaccination.

Results: We corroborate previous findings that B- and T-cell memory responses are weaker and more delayed in SOT patients than in immunocompetent (IC) individuals; however, within the SOT cohort, we found that these responses are relatively stronger and more robust in patients not receiving mycophenolate mofetil (MMF)-based therapies. Anti- spike IgG titers strongly correlated with RBD-specific IgG-producing mBc, with both displaying broad viral cross reactivity. Prebooster SARS-CoV-2-specific mBc and IL-2- producing T cells accurately predicted Nab seroconversion (AUC, 0.828) and protection against severe COVID-19. While switching unresponsive SOT patients from calcineurin inhibitors (CNI)/MMF to a low-exposure CNI/mTOR-i regimen favored wider SARS-CoV-2-specific immune responses after a fourth booster vaccination, preformed RBD-specific mBc predicted NAb seroconversion.

Discussion: Our study adds new insights into the pathobiology of immune memory and highlights the pivotal role of SARS-CoV-2-specific mBc in promoting immune protection inSOT patients.

Keywords: SARS-CoV-2; adaptive immunity; booster vaccination; neutralizing antibodies; solid organ transplantation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Flowchart of the study. (A) Observational cohort. (B) Randomized controlled trial. IC, immunocompetent; SOT, solid organ transplant; CNI, calcineurin inhibitors; MMF, micophenolate mofetil; mTOR-i, mTOR inhibitors.
Figure 2
Figure 2
(A) SARS-CoV-2-specific serological and B- and T-cell memory immune responses between SOT and IC over time before and after booster vaccination. Significant intra- and intergroup differences are shown in Supplementary Tables S1 , S2 . (B) SARS-CoV-2-specific serological and memory-cell differences at 3 months postvaccination (two doses) and at 6 months postvaccination (two doses). (C) Global qualitative SARS-CoV-2-specific immune responses at main memory compartments between SOT and IC over time after booster vaccination. SOT, solid organ transplant; IC, immunocompetent; mBc, memory B cell; IFN-γ, interferon gamma; IL, interleukin; SFU, spot forming unit. * p < 0.05.
Figure 3
Figure 3
Neutralizing antibodies against SARS-CoV-2 in serum and supernatant samples of both SOT and IC patients. (A) Presence of neutralizing antibodies against Wuhan D614g and Omicron BA.5 strains in serum samples of patients with IgG levels < 143 BAU/mL and > 143 BAU/mL. * p < 0.05. (B) Presence of neutralizing antibodies against Wuhan D614g and Omicron BA.5 strains in supernatant samples of patients with detectable NAb in serum. (C) Spearman correlations between IgG levels in serum, frequencies of mBc, and neutralization titers against Wuhan D614g and Omicron BA.5 variants in both serum and supernatant from mBc samples. All correlations were statistically significant at p < 0.05.
Figure 4
Figure 4
(A) SARS-CoV-2-specific serological and B- and T-cell memory immune responses between SOT with different IS protocols and IC over time before and after booster vaccination. Significant intra- and intergroup differences are shown in Supplementary Table S4 . (B) Global qualitative SARS-CoV-2-specific immune responses at main memory compartments between SOT with different IS regimes and IC over time after booster vaccination. Significant intra- and intergroup differences are shown in Supplementary Table S5 . * p < 0.05 is referred to the comparison made between all study groups.
Figure 5
Figure 5
Heatmap generated by hierarchical clustering of different SARS-CoV-2-specific memory immune responses for SOT and IC patients, according to the development of SARS-CoV-2-specific neutralizing antibodies (NAb).
Figure 6
Figure 6
SARS-CoV-2-specific immune-memory responses predicting NAb and severity of breakthrough infection after third booster vaccination. (A) Pre- third vaccine dose frequencies of SARS-CoV-2-specific memory B and T cells in patients developing or not NAb after third booster vaccination in previously seronegative patients. (B) The presence of pre- third dose vaccine of SARS-CoV-2-specific memory T- and B-cell responses between patients developing or not NAb after third vaccination in seronegative patients. (C) ROC curve of SARS-CoV-2-specific immune-memory responses predicting the advent of NAb after vaccination in seronegative patients. (D) SARS-CoV-2-specific serological and memory-cell immune responses in patients developing distinct severity of SARS-CoV-2 breakthrough infection. Significant intra- and intergroup differences are shown in Supplementary Table S7 . mBc, memory B cell; IFN-γ, interferon gamma; IL, interleukin; SFU, spot forming unit. * p < 0.05.
Figure 7
Figure 7
Results of the randomized controlled trial. (A) Presence of SARS-CoV-2-specific NAb (main end-point of the study) in patients from both groups of the trial after the fourth vaccine dose (T2a). (B) Presence of RBD-specific memory B - and memory T-cell responses in patients from both groups of the trial after the fourth vaccine dose (T2a). (C) Frequencies of RBD-specific mBc prior to the fourth dose (T0a) in patients with and without neutralizing antibodies after the fourth vaccine dose (T2a). Patients from both groups (A, B) were combined according to the presence of neutralizing antibodies at T2a. (D) Global qualitative SARS-CoV-2-specific immune responses at main memory compartments for both groups of study (A, B) before (T0a) and after the fourth dose (T2a). Humoral and/or cellular response means the presence of either NAb, mBc, and/or IFN-γ/IL-2 T-cells. * p < 0.05.
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