Issue #40: Vaccination versus infection: the effector and protective response

Written by Nobel Laureate Professor Peter Doherty

When we get a respiratory virus infection, the misery of increased mucus flow, sneezing, coughing and general malaise is often made worse by the pain associated with the swelling of ‘glands’ in our neck. A boil on the forearm, or bacterial infection in the hand, will likely cause us to have the same experience in our armpit. The ‘glands’ we’re talking about here are the lymph nodes (#39) where primary immune responses kick off. The pain is caused by the fact that the outer connective tissue capsule of these (normally) small, cream-coloured, kidney shaped organs contains pain receptors that are triggered when the lymph node swells.

When we’re given a vaccine by intramuscular injection in the upper arm, we can sometimes experience pain in the draining axillary nodes of the armpit. That’s because they are making an immune response and, though uncomfortable, it’s not necessarily a bad thing. What happens here is that the vaccine product is transported from the extracellular fluid as lymph (#9) that enters the concave aspect of the node via the tiny, delicate vessels of the afferent lymphatics. Much of the vaccine material will likely have been taken up (phagocytosed) by dendritic cells that ‘go with the flow’, though some may still be in free form. The current vaccines that we’re signed up for in Australia are all designed to provide the SARS-CoV-2 spike as protein (Novavax), or the genetic sequence to make that protein delivered as mRNA (BioNTech/Pfizer) or in an engineered ‘shuttle’ vector (AstraZeneca). The AstraZeneca product is currently being made here by CSL (#5).

Either the nucleic acids in the vaccine or an added adjuvant (#38) from the injected formulation (Novovax) will cause the production of cytokines, or ‘mediators’, that trigger the selective, local recruitment of large numbers of small lymphocytes from the blood (#39). As a consequence, the regional axillary nodes swell and, perhaps, become painful, while those on the other side of the body remain normal. Anyone who has after, say, breast cancer surgery, had the ‘glands’ on one side of the body stripped to limit the dissemination (metastasis) of free-floating cancer cells might ask that a vaccine be given in the other arm, or lower down the body into the gluteus maximus. 

Think of the regional lymph node as a biological processing unit that’s organised to select (#18), then expand, a spectrum of ‘fit-for-purpose’ products that are, when finished, immediately exported. The export channels are the few, big efferent lymphatics at the convex hilus (like the bit where the ureter comes out of the kidney) of the lymph node. Depending on the location of the lymph node, these efferent ‘pipes’ connect to one or other of the large lymphatic ducts (jugular, subclavian, thoracic) that, in turn, discharge into the venous blood circulation. The ‘products’ include the B cell-derived plasmablasts, the ‘killer’ CD8+ T cells, effector/helper CD4+ T cells and the memory T cells and B cells that, in the long term, traffic into tissues and in (via afferent lymph) and out of the lymph nodes.

These new ‘locked-and-loaded’, warrior lymphocytes are then pumped back through the lung, to travel around the body in the arterial circulation. If that response has been induced by, say, a non-living vaccine to the SARS-CoV-2 spike protein or mRNA, we will expect to see antigen-specific plasmablasts (activated B cells) localising to physiological sites like the bone marrow where they will differentiate further to be the plasma cells that continue to make, and pump-out spike protein-specific antibodies, or IgG molecules in the long term (#21). Such anti-SARS-CoV-2 spike protein specific IgGs will bind to, and neutralise any virus that gets into the blood. Other plasma cells will likely be making the comparable IgA molecules that, when attached to a special molecule called the ‘secretory component’ that enables transport through the epithelial barrier, find themselves in the mucus layer that bathes the respiratory epithelium.

Some IgG may also leak through from the blood into the mucus. Having sufficient virus specific IgA and IgG in the nasal cavity to immediately neutralise any incoming virus is a big ask, but there’s evidence that may have been achieved (at least acutely) with some of the COVID-19 vaccine formulations. How durable such protection might be with time is another issue, and it is likely that we will get some SARS-CoV-2 replication in the upper respiratory tract following natural infection of most vaccinated people. That’s not such a bad thing if it keeps virus levels low and limits the prevalence of human ‘super spreaders’, as it will boost the already primed (by vaccination) immune responder cells to switch to the effector phase that will eliminate the virus and, at the same time, expand the pool of memory T cells and B cells.

The process of vaccine priming before lymphocytes start to exit the node of an immunologically naïve individual may take six to 10 days, while the restimulation of the ‘just-in-time’ memory T cells and B cells expanded by earlier immunisation will happen much faster, within a few days at most. The consequence is that, apart from providing pre-existing virus-specific antibody to immediately neutralise incoming virus in mucus or blood, the time that the virus can grow unchecked and disseminate throughout the body is greatly shortened.

So, the difference between infection in naïve and vaccinated individuals all rests in numbers and kinetics. The more virus particles produced, the more cells are infected and the greater the extent of tissue and organ involvement. A week is a long time in politics and, when it comes to a fast-replicating virus like SARS-CoV-2, a week less of virus replication in a vaccinated person may mean the difference between life and death. Think about it: if a lot of lung, or heart cells are infected with SARS-CoV-2 and killer T cells (#34) suddenly flood-in to ‘bump them off’ simultaneously, we have a classical ‘kill it in order to save it’ situation.

We all understand how badly that can go. And, even if we survive that initial shock, having those tissue-invading lymphocytes stick around, along with large numbers of other white blood cells they’ve recruited, like monocyte/macrophages and neutrophils that produce some pretty toxic molecules locally, can lead to severe, persistent damage. Later, we’ll take a more detailed look at that issue of persistent inflammatory pathology. Vaccination is all about keeping it local, reducing the numbers and diminishing the damage. Next week, we’ll back track and look in more detail at what happens in the regional lymph node.