Issue #52: COVID-19 vaccines and influenza vaccines: Part 6 – viraemia and the systemic phase

Written by Nobel Laureate Professor Peter Doherty

We’ve lived with influenza all through the era of modern medicine (from the late 19th century), with our understanding of this disease being greatly enhanced by recent, rapid developments in molecular and cell biology. By contrast, our acquaintance with SARS-CoV-2 and COVID-19 dates back only 16 months and, while we already know a lot, the focus has been more on finding ways to reduce the clinical toll than on dissecting the underlying pathological processes. Still, some of that has been progressing and – as is generally the case – further illuminating the intricacies of COVID-19 will supply a ‘different mirror’ that gives insights into other disease processes, including influenza.

While SARS-CoV-2 and the influenza A and B viruses are respiratory pathogens that are known to cause major lung damage, SARS-CoV-2 is more than that. These viruses all gain entry via the upper airways where they can potentially be neutralised by virus-specific IgG in nasal mucus (#8, #21, #22), though it is a major challenge for any vaccination protocol to maintain sufficient antibody levels to protect all cells in that site (#51). Progression deeper into the lung is pretty much the whole infection story for influenza but, with COVID-19, there is the additional complication that SARS-CoV-2 RNA is frequently found in blood plasma. Any such ‘viraemic phase’ is extremely rare for flu, being recorded only for very severe cases caused by extremely virulent variants. In short, COVID-19 is a systemic infection while influenza is not.

Systemic? What does that mean? An infection is described as ‘systemic’ when the pathogen, virus or bacterium, is spread throughout the body via the blood. But therein lies an opportunity for confusion: while human flu is not a systemic infection it does have an element of ‘systemic pathogenesis’. What we’re talking about here is the circulation of biologically-active molecules – variously called lymphokines, cytokines and chemokines – many, though not all of which, are made by various cell types involved in the early, innate immune response. Optimally, these ‘pro-inflammatory’ mediators (#38) help to hold the infection for the seven to 12 days it takes for the pathogen-specific immunoglobulin (Ig) antibodies and effector T cells (#38) of the adaptive response to come on the scene. And, if all goes well, the transient presence of high mediator concentrations in the blood circulating through the brain causes our body temperature to go up (fever) and makes us drowsy and lethargic. As a consequence, we slow down and rest until we feel better.

Massive over-production of these ‘innate mediators’ in the early stages of infection with an extremely virulent influenza virus can, though, cause a ‘cytokine storm’, with increased leakage of fluid from the blood vessels into the lung. In effect, people drown in their own body fluids. Sometimes, if either an influenza virus or SARS-CoV-2 is not cleared as a consequence of immune deficiency (perhaps due to advanced age), the body tries to compensate by continuing to produce high levels of these pro-inflammatory mediators late in the disease process. Many COVID-19 patients have, in fact, been saved by the discovery that the cheap and readily available anti-inflammatory drug, dexamethasone, can, when given at the onset of this ‘hyper-inflammatory’ phase, help to reduce the extent of damage and see people through to recovery.

When it comes to the apparent difference in efficacy for influenza and COVID-19 vaccines, my current perception is that the SARS-CoV-2 products work so well because they neutralise virus in the blood and stop viraemia, the systemic distribution phase that leads to the infection of cells in the blood vessel walls (the clotting problem), the heart, the kidneys and so forth (#37). Our immune system functions normally to sustain high levels of antibodies in the blood to protect those vital organs. The antibody forming cells, the plasma cells, sit in the bone marrow where they pump out Ig molecules for years, even decades.

Historically, our most effective vaccines are against systemic infections caused by very stable viruses. To take just two: both poliovirus and measles virus initially infect cells in the upper respiratory or gastrointestinal tracts. This mucosal infection stage is asymptomatic but, once virus gets from there into the blood, it is immediately distributed to the skin (the spots of measles) and other organs, including the brain. With poliovirus, the virus can infect and kill irreplaceable large motor nerve cells in the spinal cord and lower brain, leading to respiratory or flaccid limb paralysis. Measles encephalitis can also be lethal. Vaccine-induced antibodies in the blood stop those processes from happening.

If that is indeed what the SARS-CoV-2 spike vaccines are primarily doing, then it seems that the worst forms of COVID-19 are a direct consequence of viremia. At this stage, that is by no means proven. While evidence of viraemia is more commonly found in those who are most severely afflicted, that could be either cause or effect. And we also need to know more about the possible role of viraemia in ‘Long COVID’, where people of all ages who have initially experienced asymptomatic to mild infection later develop persistent malaise, pain, debility and, sometimes, psychiatric problems. This is an emerging story that we’ll come back to from time to time through this year.