Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals

Abstract

Vaccine-mediated immunity often relies on the generation of protective antibodies and memory B cells, which commonly stem from germinal center (GC) reactions. An in-depth comparison of the GC responses elicited by SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals has not yet been performed due to the challenge of directly probing human lymph nodes. Herein, through a fine-needle-aspiration-based approach, we profiled the immune responses to SARS-CoV-2 mRNA vaccines in lymph nodes of healthy individuals and kidney transplant recipients (KTXs). We found that, unlike healthy subjects, KTXs presented deeply blunted SARS-CoV-2-specific GC B cell responses coupled with severely hindered T follicular helper cell, SARS-CoV-2 receptor-binding-domain-specific memory B cell and neutralizing antibody responses. KTXs also displayed reduced SARS-CoV-2-specific CD4 and CD8 T cell frequencies. Broadly, these data indicate impaired GC-derived immunity in immunocompromised individuals, and suggest a GC-origin for certain humoral and memory B cell responses following mRNA vaccination.

Non-Invasive Monitoring for Rejection in Kidney Transplant Recipients After SARS-CoV-2 mRNA Vaccination

“…increase in the percentage of IgM+ B-cells) were for the total pool of the analyzed immune cells, and not antigen-specific cells from each subset. Assessment of germinal center responses in the draining lymph nodes of vaccinated KTRs is likely to be more informative compared to immunophenotyping of circulating lymphocytes with regards to predicting antibody responses to vaccination (51).…”

“…This patient was one of two KTRs with documented prior SARS-CoV-2 infection. At the two-month timepoint after vaccination (median 55 days post-first vaccine, IQR [49][50][51][52][53][54][55][56][57][58], no KTRs had anti-NC antibodies but 36%, 25% and 20% had a positive result for antibodies against the spike trimer, S1 and RBD regions of wild-type SARS-CoV-2, respectively (Figure 3B).…”

Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination

“…The degree to which SARS-CoV-2 infections or different vaccines stimulate GC responses and differ in factors such as the quantity, persistence, and localization of antigen in lymph nodes (LNs) and other lymphoid tissues are important open questions. Approaches such as fineneedle aspiration (FNA) are being increasingly used to study LN-derived cells from healthy human subjects (Havenar-Daughton et al, 2020;Lederer et al, 2022;Turner et al, 2021). Disrupted LN GCs have been reported in autopsies of deceased COVID-19 patients (Haslbauer et al, 2021;Kaneko et al, 2020), while elevated frequencies of GC B cells are seen after mRNA vaccination in healthy individuals (Turner et al, 2021) and lower GC B cell frequencies after mRNA vaccination of immunocompromised individuals (Lederer et al, 2022).…”

“…Approaches such as fineneedle aspiration (FNA) are being increasingly used to study LN-derived cells from healthy human subjects (Havenar-Daughton et al, 2020;Lederer et al, 2022;Turner et al, 2021). Disrupted LN GCs have been reported in autopsies of deceased COVID-19 patients (Haslbauer et al, 2021;Kaneko et al, 2020), while elevated frequencies of GC B cells are seen after mRNA vaccination in healthy individuals (Turner et al, 2021) and lower GC B cell frequencies after mRNA vaccination of immunocompromised individuals (Lederer et al, 2022). To date, no direct comparison of LN GC histology and cellular composition, combined with measurement of viral or vaccine antigen quantity, persistence, and distribution in draining LN sites of COVID-19 patients and vaccinees has been reported.…”

Getting to the (germinal) center of humoral immune responses to SARS-CoV-2

“…By examining lymph node (LN) aspirates, Lederer et al. assessed the immune cell microenvironment elicited in healthy individuals following delivery of a SARS-CoV-2 mRNA vaccine (BNT162b2) ( Lederer et al., 2022 ). This revealed a strong adaptive response comprising SARS-CoV-2-specific GC B cells, memory B cells, Th1-type Tfh cells, and PBs in draining, but not contralateral, LNs following initial vaccination, increasing further after the second dose.…”