Issue #90 Viruses, Vaccines and COVID-19: partial protection against virus variants

Written by Nobel Laureate Professor Peter Doherty

Having discussed the events occurring in responding lymph nodes (LNs) following the prime and boost regimes advocated for SARS-CoV-2 vaccines (#81-89), we’re getting to the point where we can usefully consider what’s happening when, even for those of us who have had at least three vaccine shots, we suffer a breakthrough infection with Omicron. While this issue of partial protection has long been around for influenza vaccines it has, for both technical and practical reasons, attracted comparatively little in-depth analysis using contemporary immunology techniques.

Now, as we focus on bringing the COVID-19 pandemic to a conclusion, ‘cutting edge’ approaches are being applied and there’s the sense that studies in progress with Omicron breakthrough infections will be very informative. Obviously, it will be a while before we have that information. For now, I’ll summarise our current understanding of the SARS-CoV-2 vaccine-specific immune response and Omicron, then continue with a somewhat speculative account of what happens when Omicron bypasses that barrier and infects us.   

The mRNA (Pfizer, Moderna) and adenovirus-vectored (AstraZeneca) vaccines used to date in Australia all provide the molecular template (mRNA) to make the SARS-CoV-2 spike protein expressed on the surface of the original Wuhan virus, also referred to as the ‘wild type’ (WT) strain. The overwhelming evidence from years of research and widespread use is that vaccines work primarily by driving the generation of virus-specific, polyclonal antibodies (or immunoglobulins, Igs) secreted by the plasma cell descendants of clonally-expanded B lymphocytes. That process of rapid cell division also provides the memory B cells that divide further following a booster vaccine shot. Immediate protection following live virus challenge is mediated by neutralising antibodies that block the spike receptor binding domain (RBD) for the cell-surface ACE2 molecule, the interaction that allows SARS-CoV-2 to gain entry into our cells and take them over to become virus production factories (#20, #21, #22).

Also clonally expanded from (initially) ‘naïve’ precursors by successive vaccine shots are the effector and memory CD8+ and CD4+ T cells that recognise (#33 and #34) short spike protein segments (peptides, p) presented at the tip of our (self) cell surface MHC glycoproteins, pMHCI for the CD8+ killers and pMHCII for the CD4+ helpers (#88 and #89). The ‘helpers’ operate in the lymph nodes by providing secreted proteins (cytokines) that promote B and T cell clonal expansion and differentiation, while the CD8+ killers are the ‘search and destroy’ assassins that ‘bump-off’ the virus-producing factory cells and bring the infectious phase of COVID-19 pathogenesis (disease progression) to an end.

The spike protein of the highly infectious Omicron variant that emerged in South Africa last December to spread with super speed across the planet has at least 30 mutations that differentiate it from the original WT strain, with 15 of these being in the RBD. In general, those who have had two shots of, say, the Pfizer vaccine, are making very little neutralising antibody specific for the Omicron spike. What is somewhat surprising, though, is that the third booster dose of vaccine does seem to be inducing some protective Igs specific for Omicron. Does this reflect the massive, vaccine-induced expansion of a very few B cell clones that make cross-reactive antibodies, or the late recruitment of naïve B cells that are more cross-reactive (#89)? I don’t think we yet know that answer.

The sense many of us had with the Delta strain that preceded Omicron as a global threat, and caused the severest disease we’ve yet seen for SARS-CoV-2, is that it was a virus variant that had changed in ways that just allowed it to grow to higher titres (levels of antibodies) and, as more virus was being produced in infected people, to transmit more readily. In popular talks, I’d been using the analogy of an Olympic runner from 1900 versus 2020: reflecting the ‘evolution’ of athletics, the latter will just be a lot faster! But, while Omicron has replaced Delta, it seems that it grows less well. Something different has happened to give Omicron a ‘selective advantage’ when it comes to infecting people.

In general, the extensive modification of the Omicron spike RBD suggests that it could be an immune escape variant (#64). Furthermore, as Omicron was first detected in South Africa where there are relatively low levels of vaccination, the circulating Igs that have driven this change will most likely have been in the blood streams and/or the nasal mucus of people who have been infected with one or other earlier strain. On the positive side, it seems likely from recent evidence that the short sequences from the spike protein that form the ‘immunogenic’ pMHCI and pMHCII complexes (#33) recognised by CD8+ and CD4+ T cells have not been substantially changed by the mutations that make the Omicron strain some 40 times less likely (than Delta) to be neutralised by vaccine-induced antibodies. Is this a major factor in the partial protection provided by the current vaccines? To be continued…