Issue #89: Viruses, Vaccines and COVID-19: booster shots

Written by Nobel Laureate Professor Peter Doherty

Currently, the best protection available to any of us in this third year of COVID-19 is to have a third booster shot of either the Pfizer or Moderna mRNA vaccine. I’ll briefly review the story of how immune responses get underway from late last year (#84-88), then talk about the boosters.

When an immunologically ‘naïve’ (previously unexposed to virus or vaccine) person is ‘jabbed’ in the upper arm, the non-replicating vaccine mRNA is taken up by specialised (for antigen presentation) dendritic cells (APDCs) where it directs the manufacture of the SARS-CoV-2 spike protein ‘antigen’. As this is happening, the APDCs are travelling in the lymph that drains from the arm to the ‘filter station’ of the regional axillary lymph nodes (ALNs) in the armpit. Here, they ‘hang-out’ to ‘hook up with’ the few, naïve B and T lymphocytes that have receptors (BCRs or TCRs) specific for either the spike protein (the B cells) or for small peptides (p) bound into the tip of class I or class II major histocompatibility complex (MHC) glycoproteins. The TCRs on CD8+ killer and CD4+ helper T cells recognise these pMHCI and pMHCII complexes respectively (#29, #33, #34, #42).

In our vaccine recipients, partly as a consequence of the cytokines produced during the early innate immune response, large numbers of circulating lymphocytes are pulled out of the blood into the ALNs, which can swell up and be painful. The virus-specific immune response then gets underway when the APDCs and the lymphocytes expressing the ‘right’ (best-fit) BCRs for spike protein, or TCRs for pMHCI or pMHCII, meet up. What happens then is that these naive B cells and T cells are driven into multiple cycles of cell division (clonal expansion) and, after about a week or so, begin to leave the LNs to enter the blood stream. The circulating ‘search and destroy’CD8+ killer T cells exit into sites of infection to eliminate the virus-producing cell ‘factories’ (#34). The B lineage plasmablasts localise to bone marrow and differentiate to become antibody (immunoglobulin, Ig) producing plasma cells (#21). Other clonal progeny leave the ALNs as the long-lived memory T cells and B cells that can be ‘recalled’ to function following infection, or a further vaccine shot.

So far, I’ve described the primary immune response (#87, #88). When we give a second or third shot of the vaccine, the principal responders will now be memory B cells and T cells. Due to that initial clonal expansion weeks or months back, there are many more of these than there ever were naïve precursors. Though, with the lapse of time, these memory cells may have reverted to being ‘uninteresting’ (#41) small lymphocytes (with very little cytoplasm) they have been ‘trained’ (or programmed) in the molecular sense by going down differentiation pathways that allow them to move to ‘effector’ phase (activated killers, helpers or plasmablasts) much faster.

In summary, the supply of a new source of antigen (the booster shot) drives the memory T cells and B cells into further cycles of clonal expansion (cell division). The consequence is that, to correct for the natural processes of waning and lymphocyte loss that occur with time, a further boost gets the numbers back up for effector T cells, plasmablasts/plasma cells (and blood Ig levels) and memory cells. We don’t know how many times the booster strategy can be repeated, but it clearly works well for a second or third exposure (the one we all need now), and the Israelis are currently testing the consequences of a fourth jab.

When it comes to the CD4+ helper and CD8+ killer T cells, the TCRs on the reactivated/expanded lymphocytes following vaccine boosting will be the same as those on the memory cell that was driven back into division. We refer to each of these lineages that comes from a single memory cell as a ‘clonotype’. Looking at the ‘recalled’ response overall, the proportions of different clonotypes may vary from the make-up of the memory pool before further vaccine challenge, due to the selective restimulation of ‘dominant’ clonotypes with TCRs that bind more tightly (higher affinity) to a particular pMHC (#22).

With the B cells, both primary and recall responses develop in specialised regions of the LNs called the ‘germinal centres’. Here, the process of somatic hypermutation and affinity maturation that leads to ‘better fit’ antibodies (#22) can continue through the boosted response. But it’s not only the memory cells that are being expanded: newly emerged naïve B cell precursors can also be recruited into the germinal centres and, as a consequence, somewhat broaden the Ig response. There are further complexities regarding these secondary, or tertiary B cell responses, but we’ll save this discussion until next week when we talk about what happens with virus challenge, when vaccinated people become infected. For the moment, when thinking about boosters think, ‘getting the numbers up’!