No Thanks for the Memory

That there is "no substitute for experience" is a truism, and one that is very tempting to apply wholesale to human immunity. Indeed, we previously touched upon an particular feature of the 1918 Spanish Flu outbreak, the so-called "W-shaped" mortality impact resulting in disproportionate fatalities amongst younger adults in the 20-40 range. Some researchers theorise that older adults must have experienced an earlier influenza infection and thus gained a key immunological advantage over those not around at that time. However, our truism meets a strong challenge with COVID-19. One of the clearest and most robust observations globally is that for those infected by SARS-COV-2, it sucks to be old.

The different COVID-19 experience amongst children has been consistently observed throughout the pandemic. Firstly, children appear less susceptable to infection, while those that are infected typically present with milder symptoms, and have better outcomes than adults. UK research published in August 2021 suggests the good news also extends to the risk of so-called "Long COVID". While children can and do become severely ill with this disease, the difference in incidence of the most severe outcomes remains an active topic for research.

In a review from October 2020, Swiss researchers examined a number of hypotheses for why COVID-19 severity is lessened in the young. Their work threw the spotlight on two likely suspects, both age-related: changes in endothelial/clotting function and changes in the immune system. We will focus on the immunity side of the equation for the remainder of this post.

Grossly simplifying, humans exposed to a pathogen rely upon two main protective mechanisms. The innate immune system is the first responder, it operates to inhibit infection using generalised mechanisms such as inflammation, with little specific knowledge of precisely what it is dealing with. While the innate immune system shoots first, our adaptive immunity asks more detailed questions later, tailoring specific responses to specific pathogens based on an acquired immunological memory that grows through life. It is already known that (1) aspects of human immunity degrade with age, and (2) children rely more on their innate mechanisms, since acquisition of immunological knowledge takes time. It follows from these observations that a major thrust of current research on vulnerability to COVID-19 is around differences within the immune system at various ages.

Late last year a small study of a family with COVID-19 symptomatic parents found children had generated antibodies to a disease that had never been virologically detectable under repeated testing. It appeared as if the immune response in these children had prevented the establishment of the disease altogether. Another larger study comparing antibody responses between infected children and adults showed that children generated fewer SARS-COV-2-specific antibodies than adults, despite fewer respiratory symptoms and low incidence of acute respiratory distress. Children, in the absence of acquired knowledge, seemed to tackle the infection more robustly and effectively than those older and thought to have been immunologically wiser.

According to a group of Australian researchers, immunological wisdom might be part of the problem. Measuring antibody responses in adults and children revealed more highly specialised antibodies in the former and more general wide-spectrum antibodies in the latter. They hypothesised that the immunological memory in the elderly is more likely to deploy immune cells formed against a previously encountered everyday seasonal coronavirus. While such cells may bind to SARS-COV-2, this might be somewhat like bringing a plastic spoon to a knife fight. Children on the other hand, with their inexperienced immune system, have plenty of naive immune cells to press into action and these work from first principles to build an effective approach to clearing the virus. This hypothesis of a earlier, stronger immune response in children has been observed and measured in the clinic, such as in this study from the Montefiore Medical Center in New York.

While research offers clues, there remain open questions around why older people are quite so vulnerable to COVID-19. The elderly don't simply have older immune systems, but greater rates of obesity and other comorbidities all contribute to poorer outcomes. However, a vastly reduced number of naive immune cells and a propensity to tackle pathogens using remembered strategies may prove disadvantageous when facing the wrong kind of novel infection. We discussed thymic involution previously, and recent research shows climbing COVID-19 hospitalisation rates with age inversely mirror the exponential decline of T-cell production in the ageing thymus. COVID-19 could represent exactly the wrong kind of novelty for the adult immune system — initially deceptively familiar, but ultimately horribly different. For the elderly, handling SARS-COV-2 might require forgoing hard-won experience and returning to the immunological blank slate, only to find ageing has scribbled all over it. This seems to underscore an observation playing out globally even now: if a complacent adult immune system must learn a hard lesson, we do far better when taught by a non-pathogenic vaccine rather than a full-on viral assault.