Issue #93: Viruses, Vaccines and COVID-19: the recall and naïve responses to Omicron

Written by Nobel Laureate Professor Peter Doherty

The site of any immune response is dictated initially by where a foreign (non-self) product (mRNA, protein or peptide) is introduced into our body, then by the lymphatic drainage from that site. For a vaccine injected into the arm that’s the axillary lymph nodes (ALNs) in the armpit (#85-90), for an infection in the nose it’s (initially at least) the mucosal associated lymphoid tissue (MALT, #38) of the adenoids and tonsils and the regional cervical lymph nodes (CLNs) of the neck. Also involved from virus-invasion day one may be the small amount of nasal associated lymphoid tissue (NALT) then, as the infection spreads, the bronchus associated lymphoid tissue (BALT) and the mediastinal lymph nodes (MLNs) that drain the lung.

Once SARS-CoV-2 is in the blood (#92), the spleen and the lymph nodes draining any infected organ can also become part of the response equation. Our perceptions of what may be happening at these later stages are more inferential than they are data-based. We’ve only lived with COVID-19 for a very short time. While immunologists are deploying some fantastic new approaches to analyse the SARS-CoV-2 specific B cell and T cell responses in us, these are technologically and organisationally (#54) challenging studies that take time. Once COVID-19 is over, though, we will have a much better general understanding of how we respond to virus infections.

As things stand, much of what we think may be happening is influenced by findings from acute experiments in naïve and partially immune mice, especially following respiratory challenge with the influenza A viruses. Another lesson from ‘mouse world’ is that, if they are bred and raised under sterile (germ free) conditions, mice have no BALT or NALT. The existence of these lymphoid foci in us likely reflects prior infection with other, unrelated organisms. We can also find such lymphoid aggregates in solid tumours and in sites of chronic inflammatory pathology.

Returning to Omicron infection (#91, #92), the basic message is that the virus takes us to an immune response ‘landscape’ that is much more complex and unpredictable than that following injection with spike-protein-encoding mRNA (Pfizer and Moderna) or DNA (AstraZeneca, DNA ® mRNA ) vaccines. Whether intact or not (#92), the SARS-CoV-2 virions will, along with the spike we’ve met via vaccination, contain substantial amounts of three other structural proteins – membrane (M), envelope (Env) and nucleoprotein (NP). Of course, those who have had COVID-19 caused by any SARS-CoV-2 variant will have encountered M, Env and NP before. And the breakdown products of virus-damaged cells can provide another 24 non-structural and accessory virus-coded proteins that will be new to us. Suddenly, our virus-specific immune defences are mobilising on a much, much broader front that involves the reactivation of memory (to spike) and naïve (to everything else) T cells and B cells (#87).

So, following a ‘breakthrough’ infection with Omicron, we find ourselves in a situation where naïve B cells, CD8+ T cells and CD4+ T cells specific for up to 28 novel SARS-CoV-2 – associated proteins – or peptides (p) from those proteins (#33, #34) – are being recruited, then driven to divide (clonal expansion) and differentiate. The same should also be true for regions of the spike that differ for Omicron and the Wuhan strain used to make the vaccines. All this is happening in the same lymphoid tissue sites where those memory B cells and T cells specific for regions of the spike protein that are shared between Omicron and Wuhan are potentially being clonally expanded for the fourth (after three vaccine shots) time.

How different is Omicron? The numbers will no doubt change but, early on, the gene sequencers found evidence of some 50 mutations across the whole Omicron genome, with 30 being in the spike and 15 of those in the RBD that binds to ACE2. It’s not surprising that it takes three shots of vaccine to bring up even low levels of neutralising antibody (#21, #22) to the Omicron spike, But the spike-specific CD4+ helper and CD8+ killer T cell responses are focused on peptides that are about 85 per cent conserved, so that should lead to potent recall responses.

Measuring serum antibodies in immunologically naïve individuals indicates that infection versus mRNA vaccination gives a lower and slower spike-specific IgG response. Whether this reflects a difference in overall antigen dose (#88) or is a consequence of so many added (to spike) immune responses going on simultaneously is unclear. With regard to breakthrough infections, any ‘naïve’ B cells and T cells that are recruited into a LN environment where there is a much larger, faster and concurrent recall response by memory populations could benefit from the more rapid emergence of activated CD4+ T cells secreting the various helper factors that are essential for B cell and CD8+ T cell differentiation (#22). But there could also be negative consequence for stimulating naïve T cells specific for peptides from other (than spike) viral proteins, as the ‘recalled’ CD8+ killers would tend to eliminate antigen presenting dendritic cells (APDCs) faster. To be continued…