Issue #91 Viruses, Vaccines and COVID-19: the Omicron invasion

Written by Nobel Laureate Professor Peter Doherty

As this continues our discussion of the confrontation between the Omicron variant of SARS-CoV-2 and vaccine-induced immunity to the spike protein of the original Wuhan strain of the virus, it’s best to begin by scanning the preceding essay (#90) that summarises key background and defines the technical terms that must inevitably be used here.

Beyond that, the first thing to consider is that adaptive immunity is a highly mobile defence system (#42, #88). While the response to vaccines injected into the upper arm all happens in the axillary lymph nodes (ALNs) of our armpit, the immune effectors and memory B cell and T cell populations begin moving out within a week or so to enter the super-highway system of the blood and disseminate around the body (#86-89). For the T cells, it’s likely that the clonal expansion phase ends with the elimination of the pMHCI+ and pMHCII+ (#90) vaccine-antigen-presenting dendritic cells (APDCs), likely by the emerging CD8+ ‘killer’ T cells (#34, #35). While immune B cells exit the ALNs early, there’s also emerging evidence that maturation of the B cell/antibody/Ig (#90) response can continue for much longer in the ALN germinal centres https://www.nature.com/articles/s41577-021-00657-1. That is, though, a discussion for later, and it doesn’t change the story we’re developing here.

Large, B-lineage plasmablasts that already show evidence of substantial protein synthesis travel to the bone marrow where, settling-in to become mature plasma cells, they continuously pump out the antibody (Ig) molecules that are our front-line defence against viral invasion (#18, #21). The detection of circulating serum (the fluid phase of the blood) IgM, then IgG and IgA specific for  the pathogen, in this case the spike protein of SARS-CoV-2, has long been the first indication that a novel vaccine is working. Now, as we strive to deal effectively with the massive challenge of COVID-19, sophisticated technology is allowing immunologists to further measure the prevalence of virus-specific memory B cells and T cells in blood. As an ‘observational’ clinical trial subject (#54), I’m regularly donating 70ml of blood for two such studies from our institute alone!

So, we’ve now set the stage for what happens when a vaccinated individual circulating SARS-CoV-2 spike-specific IgG plus memory B cells and T cells is exposed to Omicron. As the vaccine has been given into the arm, there’s no particular reason to think that, apart from any IgG or IgA that has spilled over from the blood, there will be any local, virus-specific protection already set-up in the nose. When it comes to neutralising IgG or IgA antibodies specific for the Omicron spike RBD (#90), the possibility that an Omicron virus particle (virion) will encounter that in the nasal mucous of a double-vaccinated person must be very low, though – extrapolating from serum antibody levels – perhaps 20 times more likely for someone who has had three shots (#82, #90). But, as both the Ig molecules and the virions are inert particles that have to bump into each other, the probability that the spike RBD on an incoming virion will hit an ACE2+ nasal epithelial cell first seems high.

In short, if we think only in terms of neutralising antibodies, there’s not much standing between us - whether we’re vaccinated or have previously suffered COVID-19 caused by a different variant - and that initial infection with Omicron. Maybe there are vaccine/infection- induced Igs to other, more shared (than the RBD) regions of the spike protein that provide some protection. One possibility is IgG-binding to the spike of an Omicron virion could further attach a toxic complement protein that essentially ‘blows-up’ the complex (#21). Another is that a virion/IgG complex may be ‘grabbed’ by an Fc receptor (via the Fc ‘foot’ of the ‘one-legged’, Y-shaped IgG) on the surface of a macrophage, leading to internalisation and destruction in a lysosome, an intracellular organelle that serves as an ‘acid vat’ (#20). Though some researchers are now looking more closely at such possibilities, there’s currently little evidence so far that non-RBD-specific IgG binding is providing  any effective protection.

So, even if we’re triple vaccinated, there’s a good possibility that we’ll get a significant number (one may be enough) of Omicron virions up our nose and start making new virus progeny in our nasal epithelium. That’s why masking-up to stop that happening is still so important! The virus is in the air! Because Omicron is so infectious, it’s essential to ensure that a blue surgical mask fits closely, especially over the nose and around the cheeks. A further possibility for high risk environments is to wear a cloth mask over a well-fitted surgical mask. In any case, if you re-use masks, rotate them over several days and, if possible expose them in direct sunlight for a few hours. Once the virus is in, whether it’s 10 or 10,000 new infectious virions that are produced in our nose over the ensuing hours, the disease process is ‘up and away’. To be continued…