Greg writes:
Dear Vincent and co-hosts. I started listening to TWIV many years ago when I first learned about the podcast while attending ASV 2017 in Madison, WI, However, I must admit that I rarely miss an episode these days and listen with great interest; especially when the discussions pertain to SARS-CoV-2. Thank you also to Dr. Daniel Griffin for the clinical updates as well!
Today, after hearing you discuss this recent paper (along with your invitation for those with questions or comments to write), I decided today would be the day that I take the time to write and share my own comments.
First, I want to offer my highest praise for Microbe.TV and the great service you and your co-hosts (TWIV included) are providing through these podcasts. I, for one, really enjoy the banter between co-hosts and the episodes guests, and the discussions of local weather conditions in general. Moreover, I enjoy the discussion of “data”. whether it is only a brief snippet (Stef – your snippet was not so short!) or a more detailed “journal club-style” figure by figure discussion.
Second, I consider myself knowledgeable in the field of B cell Immunology and specifically the literature demonstrating that circulating antibody titers (IgG in blood) wane over the course of months either following SARS-CoV-2 infection or prime-boost COVID-19 mRNA vaccination. To this end, I wanted to offer a small but important clarification on the terminology being used in this episode as it relates to B cell memory. Specifically, a productive T-cell dependent (TD) B cell response that leads to a fruitful germinal center reaction will yield BOTH GC-derived memory B cells (many of which are class-switched and possess somatic mutations of their IgH/IgL) AND terminally differentiated antibody-secreting cells (plasmablast/plasma cells) – so of which will take up long-term residence in the BM (or other suitable niches).
As it relates to the bone marrow resident plasma cells, the so-called LLPC compartment that was the topic of Nguyen et al, these cells represent “Wall 1 of adaptive humoral defense” (borrowing the terminology of Akkaya, Kwak and Pierce (PMID 31836872); especially when one considers timepoints after the first few weeks when IgG produced by short-lived “plasmablasts” has declined and we are considering the “titer setpoint” for a particular donor. Since IgG in blood has a relatively short half life of 3-4 weeks, the maintenance of stable antibody titers in blood requires ongoing Ig production by ASC and continuous replenishment. The apparent waning of serum IgG titers in convalescent or vaccinated subjects that has been well-documented in the literature is certainly in line with the data published by Nguyen and co-authors in which Spike-specific ASC are not entering into the LLPC compartment (based on their classification via surface CD19 expression). However, as it relates to B cell memory, there is also ample data (including data my group has reported – PMID 36429090) that confirms the generation of Spike-specific memory B cells (and at quite high frequencies) in subjects despite their low Spike-specific IgG titers in blood.
To my point…while the data presented by Nguyen and co-authors indicate Spike-specific IgG+ ASC are not entering into the LLPC pool (based on phenotype), it is important to note that natural infection or COVID-19 mRNA vaccination are both capable of eliciting robust memory B cell responses. To echo Stephanie’s point, circulating IgG titers and/or the abundance of Spike-specific IgG+ ASC in BM does not provide any (useful) information on the level of neutralizing immunity conferred by Ig(A) at the mucosal interface where SARs-CoV-2 virus infection (first) occurs. Moreover, if given the choice (assuming we are offered one…) I would rather possess a clonally expanded memory B cell compartment (along with memory T cells) that are capable of re-engaging in an adaptive immune response and undergoing further affinity maturation via somatic mutation than a population of “stable” BM-resident LLPC that, while capable of secreting tremendous quantities of antibody for decades…, are unable to refine their fine specificity and “adapt” to emerging variants…the ones that are responsible for re-infections.
Said differently, while the apparent inability of Spike-specific ASC elicited through mRNA vaccination to join the LLPC compartment is concerning…such cells only contribute to “Wall 1” of acquired humoral defense and in the ideal scenario such Ig can/will prevent (re-)infection…but that is not our reality and a nearly unattainable bar to achieve for the COVID-19 vaccine (or for a seasonal influenza vaccine as well)! Instead, it is “Wall 2” (memory B cells) generated following a (primary) infection or vaccination that are most likely to impact the outcome of a future (breakthrough…I know you don’t favor this terminology) infections…when pre-existing antibodies FAIL to provide sterilizing immunity!
Returning to the paper of discussion, it remained to be demonstrated whether the BM aspirate donors possessed “stable” memory B cell populations….maybe such work is already “in the works” and is certainly of personal interest.
In closing, I really enjoy listening to the show and I look forward to (potential) future interactions with you and your co-hosts. I had the privilege of speaking with Cindy at AAI24 and I waved to Brianne as we passed each other on the escalator… and I am still holding out hope that Stephanie will (re-)invite me to give a guest lab meeting at CWRU (yes – I called you out Stef! )
Kind regards,
Greg Kirchenbaum PhD