By Mariana Bego

Many respiratory viral infections, such as the seasonal flu, target the two most immune-vulnerable populations, younger children and seniors. However, when it comes to COVID-19, the risk for severe illness increases with age, with seniors at highest risk while younger children appear significantly more protected. In addition, the dynamics pattern of age-specific COVID-19 mortality mirrors other major causes of death which affect older people, such as chronic illnesses and cardiovascular disease. The reason behind this puzzling phenomenon is still unclear.

A new study led by University of Melbourne scientists describes functionally distinct antibodies against coronaviruses (CoV) in children and older adults. Antibodies are key components of the immune response needed to control most viral infections. While we often talk about the neutralizing capacity of antibodies as preventing the virus from infecting naïve cells, they do have many other very equally important functions. The non-neutralizing roles of antibodies are often linked to their Fc region and known as Fc-mediated functions. For these roles, antibodies mostly act as ‘danger flags,’ alerting the immune system of the infection. Antibodies bound to viral proteins on the outside of infected cells tag these cells for destruction, antibody-labelled viral particles are rapidly detected, and then engulfed by specialized immune cells. However, this study shows distinct antibody signatures with differential functional implications, based on the person’s age.

The authors first present evidence of markedly different antibody signatures between samples from pre-pandemic times, both from healthy children and seniors. They defined features used to characterize the antibody signatures. These features include: 14 antibody detectors (like antibody isotypes, subclasses, and the characterization of their Fc region) and their reactivity to 14 coronavirus antigens (including endemic/pandemic and seasonal viruses). The final composite dataset made up of 196 individual components (14 detectors x 14 CoV antigens) was generated from the plasma of 89 children, 98 adults and 57 seniors. Of the 196 components, 58 (30%) were significantly different between children and seniors. More specifically, IgA and IgG antibodies directed against a range of CoV antigens were observed in healthy seniors, while healthy children displayed mostly elevated SARS-CoV-2-specific IgM, with distinctive Fc-mediated functions. The authors suggest that children have fewer exposures to seasonal coronavirus, resulting in less experienced but more reactive antibodies. The authors’ age-dependent analysis of COVID-19 patients confirmed elevated class-switched antibodies (from IgM to IgG) in seniors, while children had stronger Fc responses, which they showed to be functionally different.

Overall, the authors conclude that differences in antibody signatures between children and seniors are likely primed by their prior exposure(s) to circulating seasonal CoV, possibly contributing to their differential clinical outcomes to COVID-19. They suggest that children benefit from their less-experienced immune status prior to SARS-CoV-2 infection, which provides them with the ability to make a more functional antibody response against SARS-CoV-2.

 

Selva, K.J., van de Sandt, C.E., Lemke, M.M. et al. Systems serology detects functionally distinct coronavirus antibody features in children and elderly. Nat Commun 12, 2037 (2021). doi:10.1038/s41467-021-22236-7