Issue 96: Viruses, Vaccines and COVID-19: ending the infection and ‘calming down’

Last week (#95) we discussed how the capillary bed of the terminal lung alveoli – where the RBCs receive O2 and give up CO2 – gets ‘first dibs’ on newly minted immune effector cells and antibodies. The oxygenated blood then returns to the right side of the heart via the pulmonary veins to be pumped around the body via the much more powerful left ventricle. As with every other tissue, the lung must access oxygenated blood that comes in at about six times the pressure (of the pulmonary artery supply #95) via the bronchial arteries. These blood vessels travel with, and branch with, the lung bronchi, to end finally in the capillaries and post-capillary venules, where most extravasation of molecules (like circulating Igs #19, #20, #21) and recently stimulated, ‘activated’ B and T lymphocytes is likely to occur (#94). As this happens, every region of the lung that is supporting virus replication can now be a site of acute damage by incoming CD8+ killer T cells as they eliminate the virus-producing ‘factory’ cells. Obviously the more effectively that vaccination limits the extent of earlier virus dissemination, the better our lung function will be.

That same argument applies to the rest of the body – including the sites of initial virus invasion in the nose and oropharynx – as the arterial circulation distributes immune cells and Igs everywhere. The exception may be the brain, where the blood/brain and blood/CSF (cerebrospinal fluid) barriers may, unless damaged, exclude circulating Ig molecules and B cells, though maybe not memory T cells. So far, analysis of CSF samples from COVID-19 patients indicate that it is unusual to find SARS-CoV-2 specific IgG, leading to the interpretation that direct infection of the brain is not the rule.

Still, what’s going on in the brain in COVID-19 is far from clear. Brain scans of mild to severe COVID-19 cases infected with earlier strains show some evidence of shrinkage, particularly in regions associated with olfaction (#11). A positive sign is that loss of sense of smell is much less common with Omicron than with other SARS-CoV-2 variants.

Otherwise (in vaccinated people suffering a ‘breakthrough” Omicron infection) plasmablasts derived from newly-engaged immune B cells can potentially, along with those recalled from vaccine-induced memory that are cross-reactive (for the spike protein), localise to – and begin virus-specific Ig production in – any site of virus-induced damage and/or the lymphoid tissue draining such sites. It’s clear that this is happening in the lung, and that these localised plasma cells are pumping out a lot of antibody. This should also be true for the nose but, if that is the case, there is early evidence that at least some people who have been infected with, and recovered from, the BA.1 Omicron variant are now being ‘super-infected’ with the further-mutated BA.2 strain. The Danish study reporting this states that the problem is relatively rare and that most of these mild ‘second Omicron’ cases were in young, unvaccinated people, but there’s no clarity yet on whether prior vaccination does indeed limit the problem.

Overall, as virus specific Ig molecules and ‘killer’ T cells do their ‘search and destroy’ job around the body, symptoms could be transiently worse but then soon recede. In general, though there may be other factors driving the persistent symptoms of Long COVID (a topic for future discussion), the general theme with most virus infections is that, once the pathogen is eliminated the recovery process begins. Some of the T cells that have localised to sites of virus-induced pathology, or to nearby mucosal associated lymphoid tissue like the NALT and the BALT (#93) may stay in the region as ‘resident memory’ T cells, while Ig-producing plasma cells may continue to pump out protective antibodies in the long term. Beyond the site of product delivery, this continuing local immunity profile is not, of course, a characteristic of vaccination. Perhaps we might achieve such outcomes if, for instance, we administered ‘attenuated virus’ (#48), or the SARS-CoV-2 spike (protein or mRNA #44) with a ‘puffer’ or spray up the nose, but this approach has not emerged during the current pandemic.

Once the virus and viral antigen is eliminated, many of the highly activated CD8+ ‘killer’ T cells will just die-off and the numbers in blood will rapidly fall. They need to go: even though these activated ‘effectors’ are tightly targeted (by the need to interact with pMHC1 complexes, #34, #94) to infected cells and will not damage normal tissue nearby, they may still be secreting bioactive cytokines and chemokines that, traveling via the blood to the brain, can contribute to a general sense of malaise. Basically, once the virus is gone from the body, we would normally expect the immune response to ‘calm down’, any virus or immune-associated damage to repair – so far as that’s possible – and people to soon feel better. That’s likely true for the majority, but then there’s Long COVID. Having covered the ‘best case’ scenario (#93, #94, #95), there’s a lot more to be discussed.