Title: Boosting vaccine responses in older persons
Funder: Dunhill Medical Trust

Abstract: Ageing negatively impacts the function of the immune system (Boraschi et al., 2013, Goronzy and Weyand, 2013, Geiger et al., 2013, Kollmann et al., 2012), resulting in increased susceptibility to infections and infection-related morbidity and mortality in older people (Dorshkind et al., 2009). Vaccination is an effective intervention that can prevent infections, however older individuals often do not generate protective immunity after vaccination, resulting in an increase in vaccine-preventable infectious disease in the older members of our communities (Govaert et al., 1994b, Ortqvist et al., 1998, Stiasny et al., 2012, Burns et al., 1993). However, the biological reasons for the decline in the immune response to vaccination with age remain poorly understood (Govaert et al., 1994b, Govaert et al., 1994a, Frey et al., 2010). Our research aims to determine the cellular and molecular mechanism/s that underpin the poor response to vaccination in ageing. At the heart of the response to vaccination is the germinal centre – a dynamic structure that forms in secondary lymphoid tissues after immunisation, and produces long-lived plasma cells, which secrete antibodies that block pathogens from establishing an infection, and memory B cells. It is these cells and their antibodies that provide protective immunity after vaccination. With age, the magnitude of the germinal centre response decreases (Szakal et al., 1990, Kosco et al., 1989, Zheng et al., 1997) resulting in decreased protection against subsequent infection (Lu and Cerny, 2002, Han et al., 2003). Dendritic cells are required for germinal centre formation: they act as antigen presenting cells and activate CD4+ T cells, which enables their differentiation into T follicular helper cells. These cells are essential for the initiation, maintenance and quality of the germinal centre response (Vinuesa et al., 2016). Our research has identified that dendritic cells are not properly activated in aged mice after vaccination due to reduced responsiveness to type I interferon (IFN-I). Importantly, enhancing IFN-I production at the time of vaccination can boost the defective T follicular helper cell and germinal centre responses in two-year-old mice (Linterman Lab, unpublished), suggesting that boosting IFN-I may be a rational strategy to improve vaccine responses in ageing. The research proposed here aims to determine whether the increased responses to IFN-I are associated with enhanced T follicular helper cell and antibody responses after vaccination of older persons. These experiments are required to determine whether manipulating IFN-I production is a rational strategy to improve efficacy in older people.

Lay abstract: As we age the function of our immune system declines. The impact of this is two-fold: we are more susceptible to infections and less able to generate protective immunity after vaccination, further increasing the risk of infection. For example, it is estimated that ~75% of deaths from seasonal influenza occur in people over 65 years of age, and ~65% of influenza-related hospitalisations occur in people from this age group. Therefore, there is an urgent need to improve the effectiveness of vaccines, such as for seasonal influenza, in people over 65. Public Health England estimates that a better seasonal influenza vaccine for this age group would result in 30,000 fewer general practitioner consultations, 2,000 fewer hospitalisations and prevent more than 700 deaths each year in England alone, thereby improving health and quality of life for persons over 65 and alleviating the workload associated with this disease on National Health Service. My laboratory works to understand why older bodies do not respond well to vaccines. To do this we do research in both mice and in humans, to combine the tractability advantages of mice with the physiological relevance of studying humans. In our mouse studies we have discovered that decreased responsiveness to a particular chemical messenger, produced by the body after vaccination, is responsible for a diminished response to vaccination. Importantly, by stimulating production of this chemical messenger in aged mice we can improve the response to vaccination. The next step for this work is to determine whether increased responsiveness to this chemical messenger can improve vaccine responses in older persons, and this is the project we are asking to be funded by the Dunhill Medical Trust. This is a proof-of-concept study which, if successful, will inform ways to improve vaccine formulations to enable older bodies to respond better to vaccination.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;3.4 VACCINES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM