There was a real, measurable shift in the peak season for several endemic human pathogens as well as a rebound in infections, coinfections, and disease severity among them after the COVID-19 pandemic’s restrictions on human mixing were lifted. To create a conversational phrase for this, the term “Immune Debt” was coined. This term wasn’t well understood and was also misinterpreted, changed and criticised by some in public and scientific circles. Mind you, the hypothesis underlying the term remains an accurate one. “Immunity Gap” was also mentioned, and then “Immune Shortage“. All of these can be easily misinterpreted by a chunk of the population. And they have been. But interestingly, the underlying initial definition has not. Could it be that it’s a mistake to make a new term for the outcome rather than the cause of the changed infection patterns?

What is being defined?

During the early days of the COVID-19 pandemic, various countries implemented various methods to prevent human contact. Human mixing is how respiratory viruses spread – especially when we share contaminated air spaces and moreso when we are close, where exhaled particle density is highest.

Some countries took extreme measures very early and were successful in keeping SARS-CoV-2 out. They went so far as to shut their external and internal borders and ensured most of the population remained in place at home until 80% or more of them had been vaccinated. Frontline workers and childcare were still needed, however, and this maintained some circulation of endemic respiratory and gastrointestinal pathogens. New Zealand and Australia were examples of this approach. It saved thousands of lives while a layer of anti-SARS-CoV-2 immunity was created.

One of the side effects of these effective non-pharmaceutical interventions (NPIs) was that the circulation of other pathogens – viruses and bacteria – was also reduced. In one great outcome, so effective were these NPIs that one virus appears to have been eradicated from the planet (except for laboratory freezers) – the influenza B Yamagata lineage.

What is “Immunity Debt”?

For a time – and that time varied by country – there were far fewer circulating RSV, MPV, Streptococcal and other infections.

Briefly, let’s talk about something that’s assumed in expert circles but probably not discussed enough outside them, which is that endemic pathogens reinfect us, often without us realising it. They may cause an asymptomatic infection or a short and mild clinical impact that we usually overlook. A sniff (“it’s allergy season”), a cough (it’s the cold air”), or a headache (I slept with my neck at a funny angle) that may be gone by the next morning.

Now I need to be reeeeeally clear before proceeding. I’m NOT saying that the human immune system NEEDS these infections to exist or function “better”. It does not. It’s not a muscle that needs to be worked out. I don’t know where that inane idea came from, but, for the record, it was not part of the definition of the immune debt. The hugely complex, multilayered human “immune system” exists already. It’s able to respond to any new foreign object encountered precisely because it’s already kitted out with everything it needs. Infection prompts the immune system to respond, create a memory, and be better able to defend the body against the pathogen in the future, because it will meet it again in almost all cases. You may never meet a member of the genus Orthoebolavirus, but your immune system is already a little prepared if you do. Infection is not disease, as immunologist Marc Veldhoen recently noted

NPIs affected us in a few ways.

1. Babies were born with as-yet-uneducated immune systems, and other young children had, by luck, not had their first exposure to the “usual” pathogens. They entirely missed their first infections with RSV, MPV, Pathogen C, D, E and a rainbow of other potential nasties. When they were eventually infected after the NPIs lifted, they probably had less immune protection (waned maternal antibodies or no usual prior immunity) than normally expected by that age, so a surge or more-than-usual infections, including a higher number and proportion with severe outcomes, meaning children’s hospitals may have been busier or even overwhelmed.
2. Children and adults who missed out on repeat infections by a range of different pathogens that they’d been infected with earlier in life. Reinfections may normally go unnoticed, as discussed above. However, the immune system still gets a prompt to produce more antibodies and activate cellular memory to clone a few more defensive cells, all to better defend against that familiar pathogen. Without reinfections, a similar outcome of waning immunity may lead to higher numbers of and more severe infections.
3. In populations with weaker NPIs or none, pathogens continued to infect, circulate, mutate, and travel via infected hosts. They were one source for the world as it opened up. Another was from the frontline workers who were needed to keep shelves stocked and the lights on.
4. With antibody-based immunity decreasing across most of a previously NPI-protected population, more people could be infected simultaneously after people began mixing again. This may extend to infections requiring a lower dose of pathogen A, B, or C because there were lower levels of antibodies to pathogen A, B, or C to defend against each invader. So more people may have been infected than normal. Bigger seasons.
5. Pathogens continued to mutate, so when human mixing recommenced, we may have been faced with increased pathogen novelty. Given that pathogens evolve in ways that improve their ability to keep doing their thing, they may have drifted further from any older restraining immunity. Combined with waning immunity, this novelty could have been the major driver for epidemics of those most changed pathogens being shifted from their usual start and peak times to new times, as we experienced.
6. Some pathogens interact positively, some negatively. For example, a preceding influenza infection may be followed by Streptococcus pneumoniae, Staphylococcus aureus or Streptococcus pyogenes infection – these are examples of positive interactions. Other pairings like this exist where viruses and bacteria are found to occur together more often than by chance alone. This may be due to opportunistic bacteria making the most of tissue damage by a preceding viral infection, or it may be due to more specific molecular interactions. Rhinovirus and RSV infections can also precede bacterial infection. Now, magnify those bacterial secondary infection effects due to a larger and perhaps more severe influenza, rhinovirus, RSV and other pathogen seasons.
7. A side-effect of the co-occurrence of multiple pathogen epidemics is that coinfections – detection of more than one pathogen at the same time (differing from one infection following another, as we just discussed for bacterial secondary infections) – can increase. It’s still unclear whether coinfection produces worse outcomes than single infections, though, so this is often an academic point.

The reality of being immune isn’t a legal one

Not noticing when we get infected leads us to cry, “I never get the flu!!”. The reality is far from that.

Your body’s response to an infection is to develop immunity. Not immunity in the legal sense, but in the much more complex and biological sense. You do still get infected, but usually with a milder outcome. And each of those infections can “top up” or energise that pre-existing immunity you developed from the first infection you had. That first infection may have been a doozy and is more likely to be symptomatic than subsequent infections by the same pathogen and its variants.

Every time there’s an infected person or contaminated air space or surface near you, there’s a chance you’ve come away with a new pathogen in your system. Even if you never notice it, your immune system does, and it is reminded by it, which is why you never notice it!

NOTE Vaccination also produces an immune response, but without the risk of a wild virus replicating inside you at full efficiency. But sometimes a vaccine doesn’t generate the same range and scope of immune response as a wild infection; that’s more about the need for a better, safer vaccine, though. But this isn’t a reason to allow yourself to get infected instead – that always carries more risk of harm than immunisation using a well-tested vaccine.

Use a term that notes the cause before the effect?

Frankly, there’s been a cringeworthy amount of focus on the term used to describe the waning and late immunity driven by COVID-19 pandemic NPIs. However, those arguing all seem to agree on what happened and most likely why.

There is also the camp that believes this is all due to SARS-CoV-2 creating so much immune dysregulation that it paved the way for earlier, bigger and more severe epidemics of multiple pathogens. Here are two reasons why this doesn’t work for me. Firstly, there is evidence to support the mechanism – RSV antibody immunity has been shown to wane during the NPI period. These authors proposed this as a driver of unusual seasonality, even though cellular immunity didn’t drop off. Antibody immunity plays a role in reducing the virus’s infection capability. Secondly, New Zealand and Australia had reported big shifts in RSV seasons before SARS-CoV-2 had been allowed to swarm their jurisdictions.

So, to continue the cringe, I propose another new term!😉

Infection Pause

This describes what caused the waning immunity and the missed infections: a reduction in circulating infections. The outcome affected immunity. It also uses words that I think scientists and the public are on the same page about.

We probably all agree that there were fewer infections for a period and that timespan correlates with the NPIs being in place. A pause of infections.

I’m out.

P.S. Thanks to my partner, KA, for active discussions about this topic, leading directly to this idea.❤️