The novel adjuvant, ADA-1, restores age-associated defects in the adaptive immune response to Clostridioides difficile infection and vaccination in an aging mouse model

Abstract

Abstract Clostridioides difficile is the leading cause of healthcare-associated infection in the United States. The elderly (≥65) have the greatest risk of C. difficile infection (CDI), severe morbidity, and mortality due to CDI. Though antibody responses against C. difficile Toxin A/B (TcdA/B) following primary infection or vaccination are protective against symptomatic disease, the elderly have impaired humoral responses. Using an aging mouse model, we show that there is significantly greater morbidity and mortality in aged mice during primary CDI compared to young adult mice, as seen in elderly CDI patients. Additionally, during both primary CDI and vaccination against TcdA/B, aged mice have significantly lower anti-TcdA/B antibody titers. This impaired humoral response is the result of poor Tfh and B cell responses following infection and vaccination as aged mice have a significantly lower frequency of Tfh cells and number of anti-TcdA/B B cells compared to young adult mice. While these age-associated defects in the humoral response allow for increased vulnerability to CDI, we show that these defects can be restored with the addition of the novel adjuvant ADA-1 during vaccination of aged mice with TcdA/B-encoding DNA. With ADA-1, the anti-TcdA/B antibody response in aged mice is restored to levels seen in young adult mice. ADA-1 also boosts the frequency of Tfh cells in aged mice following vaccination, suggesting that ADA-1 can restore the development of the aged germinal center reaction following vaccination. As such, this work highlights both the need for the development of a C. difficile vaccine with the elderly in mind and presents ADA-1 as a solution to overcoming age-associated defects in the vaccine response of the elderly. Supported by Department of Defense Grant: W81XWH0910382 Pennsylvania Department of Health CURE Grant