Issue #94: Viruses, Vaccines and COVID-19: heading on and out to search and destroy

Written by Nobel Laureate Professor Peter Doherty

Following an Omicron ‘breakthrough’ infection in a vaccinated individual, the linked processes of clonal expansion and differentiation towards ‘effector’ phase (#91-93) continue in the draining lymph nodes (LNs) for ‘recalled’ memory (vaccine primed) and naïve (unique to Omicron) T cells and B cells. This ‘stimulus phase’ likely ends when the viral antigen-presenting dendritic cells (APDCs) are eliminated by the CD8+ killer T cells. Within days – maybe four to six for the memory sets, seven to ten for the naïve – the progeny plasmablasts (B cells) and ‘activated’ T cells begin exiting the LNs to join the circulating white blood cell (WBC) pool. Departing via the thin-walled efferent lymphatics, the lymph flow carries them to the large lymphatic ducts that discharge into the right or left subclavian vein.

Some of the activated B cells will stay behind in LN germinal centres (GCs), perhaps held there by the persistence of viral protein on the surface of specialised follicular DCs. Here, they continue to differentiate and make ‘higher quality’ antibodies (#22). Other virus-specific B cells never enter the ‘nursery’ of the GCs, but are quickly mobilised in the ‘extrafollicular’ regions of the LNs to provide short-lived plasma cells that pump out a lot of virus-specific antibody, or immunoglobulin (Ig), fast (#21). In a vaccinated individual, it would be great if those first antibodies come from the few memory B cells expressing Igs that are cross-reactive for the vaccine-delivered spike protein and that of the substantially different (#93) Omicron variant, though I don’t think we yet know if this is the case. Otherwise, the naïve B cells specific for Omicron will likely be slower to transition to being Ig-producing plasma cells.

Obviously, the closer the ‘match’ between the vaccine and the pathogen, the faster we will see the substantial production of those Ig molecules that can ‘grab hold’ of the spike and ‘tag’ the virus for possible destruction or, better still, block the receptor binding domain (RBD) and prevent (neutralise) entry into vulnerable cells. The Delta strain of SARS-CoV-2 is ‘closer’ antigenically to the spike in the vaccine, and triple vaccination clearly protects better against the initial infectious phase with Delta than with Omicron. Also, produced after infection but not spike vaccination, will be antibodies to the M and ENV proteins (#93) on the surface of the virus particles (virions), though it’s not yet known if these are of any protective value. And infection can potentially lead to the production of Igs specific for any of the other 25 virus-associated proteins, including the nucleoprotein that is inside the virion. Perhaps some of these Igs help at the ‘clean-up the debris’ stage after virus infected cells are destroyed, but it’s unlikely they are of much benefit re protection and/or recovery.

Where exposure to these other (than spike) proteins is undoubtedly of value is to stimulate T cell memory to a much broader spectrum of viral peptides presented in the cleft of cell surface class I (CD8+ T cells) or class II (CD4+) MHC glycoproteins (#33, #34). That might suggest that the preferred option is to be infected rather than vaccinated. But, if the virus does indeed catch up with you, being triple vaccinated means that that you are at much less risk of severe disease and even death. Also, we don’t know if a lot of that ‘irrelevant’ Ig response to components that are not on the surface of the virus is ‘good’ or ‘bad’, and there’s always the risk of making cross-reactive antibodies that could cause autoimmunity. Vaccination is obviously the way to go but, if you do suffer a breakthrough Omicron infection, there is the comforting thought that you may soon be ‘super-immune’. Courting infection could, though, be a bad strategy, especially for those who are older and/or have co-morbidities. And, even for the vaccinated, there’s still some risk of Long COVID.

Returning to our ‘activated’ effector T cells and B cells that departed the LNs and made their way to the subclavian veins. Entering the venous circulation, they soon find themselves in the right atrium of the heart, then the right ventricle to be pumped into the vasculature of the lung, along with the much more numerous erythrocytes (RBCs) that exchange CO2 for O2 at the capillary vasculature of the terminal alveoli. By this time (say four to ten days after the initial virus exposure) at least some lung epithelial cells will likely be infected with the Omicron virus. And other WBCs, especially neutrophils and monocyte/macrophages, will have earlier encountered molecular changes in the walls of the lung capillaries that induce them to leave the blood (#39) and establish sites of virus-induced inflammatory pathology. Once our ‘front-line’, virus-specific T cells and B cells come on the scene, at least some will ‘see’ (as chemical gradients #35) those same ‘exit signs’ and push their way between vascular endothelial cells to join the battle in the lung. To be continued…