Investigating clonal hematopoiesis as a driver of respiratory morbidity, infection risk, and vaccine-related immune dysfunction

Clonal hematopoiesis (CH) is a condition that emerges as we age, affecting more than one in ten adults over 65. In CH, a significant portion of an individual's blood cells are made from a single, abnormal stem cell, increasing the risk of cancer, chronic disease, overall infection, and early death. While research has shown that CH disrupts immunity, we still do not fully understand its impact on the lungs, infections, and vaccine responses. These gaps are critical because lung infections and disease are leading global causes of hospitalization and death in older adults. Vaccines are key preventative tools, but they rely on strong immune responses, which may be compromised. Thus, our project will study whether CH is linked to a greater risk of lung disease and infections, and how it may shape responses to vaccines or immunotherapies. First, we will analyze large-scale health databases to test whether people with CH are more likely to have asthma, COPD, influenza, or COVID-19; and whether they face worse outcomes like hospitalization or intensive care. We will also explore whether CH contributes to frailty, a major risk factor for poor recovery after infection in older adults. Second, we will use blood samples from influenza and COVID-19 vaccine trials to measure whether people with CH mount weaker immune responses, and whether stronger doses or alternative strategies could improve protection. Finally, we will extend this work to cancer immunotherapy by studying whether CH alters responses to BCG, a vaccine-based treatment for bladder cancer. Together, this study will deliver the first comprehensive understanding of how CH shapes lung health, infection risk and vaccine response. The results will enable identification of high-risk older adults, inform optimized vaccine strategies, and guide new therapies targeting CH. Ultimately, this work will help ageing populations live longer, healthier lives with fewer hospital visits, while easing strain on the healthcare system.