Improving vaccines for the elderly by blocking inflammation
By studying skin immunity decline in old age, researchers found that an anti-inflammatory pill could help make vaccines more effective in the elderly.
The study, published in The Journal of Allergy and Clinical Immunology, found that an excessive inflammation reaction in older people can obstruct the immune system.
We know that the immune system declines with age, and people can be affected by pathogens they were once immune to. We found that when it comes to cutaneous immunity, the immune system was being obstructed by skin cells that were too prone to producing inflammation responses. We’ve now identified a way to block that inflammation in the short term
To investigate immune responses, the researchers injected an antigen – a derivative of a pathogen that creates an immune response without inducing illness – into the skin of 175 participants (78 were over 65 years old and the rest were under 40). The pathogen was the Varicella Zoster virus (VZV), which causes chicken pox.
After a person contracts chicken pox, they become immune to VZV, but it can re-activate in old age and cause shingles if T cell immune responses aren’t strong enough. All study participants had previously had chicken pox, meaning they should be immune.
The researchers found that the older subjects exhibited weaker immune responses, as there was less T cell activation, and less reddening and swelling of the skin. The reduced response was not due to a lack of resident memory T cells present in the skin.
As a control, they also injected a benign saline solution into the other arm of each participant. The researchers noticed that even the saline solution brought about an inflammation response in some of the older participants. Those who had the strongest inflammation response to the saline solution had the weakest immune responses to the VZV, suggesting that the excessive inflammation was inhibiting VZV-specific immunity.
By analysing skin biopsies post-injection, the researchers found that the excessive inflammation was associated with activation of the p38 MAP kinase pathway. To test whether this enzyme was to blame, they conducted a follow-up test with 18 of the over-65 participants, who took Losmapimod, a drug that inhibits the enzyme in order to reduce acute inflammation responses. While the drug was designed for long-term use and has been trialled for treatments of Chronic Obstructive Pulmonary Disease (COPD) and arthritis, the participants only took the pill for 4 days, before once again being injected with the VZV antigen.
Losmapimod treatment successfully increased the immune responses to the VZV antigen.
A short-term blockade of the inflammation response opened up a window of opportunity for the immune system to respond effectively
The researchers are currently planning a follow-up study which will test whether a flu vaccine is more effective for the elderly when combined with brief use of Losmapimod.
We have shown how excessive background inflammation in the elderly can affect the ability of the immune system to respond to pathogens or vaccines. By comparing gene expression in the skin of young and old people we were able to identify the immune cells which appeared to be causing this abnormal inflammation. Importantly, this study shows how certain drugs could be used to prevent this excessive inflammation and enhance immunity in the elderly.
The study was conducted by researchers at UCL, The Roslin Institute, Rockefeller University, the Royal Free Hospital, the Francis Crick Institute, and the Agency for Science, Technology and Research, Singapore.
The research was funded by the Medical Research Council, Dermatrust, the British Skin Foundation and the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Losmapimod was provided by GlaxoSmithKline (GSK).
Milica Vukmanovic-Stejic et al, ‘Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation’, The Journal of Allergy and Clinical Immunology 2018. DOI: 10.1016/j.jaci.2017.10.032
Infection & Immunity Research Division
Control of Infectious Diseases Institute Strategic Programme