DCS - An investigation to enhance immunity to influenza in elderly individuals through reversal of the immune senescence

Lead Research Organisation: University of Birmingham
Department Name: Cancer Sciences

Abstract

Flu is a major health concern and although flu vaccination is given every year to people over the age of 60 years, a lot of people make a poor immune response to the vaccine. It is now clear that one reason why older people can develop problems with their immune system is that they carry chronic viral infections such as cytomegalovirus (CMV). The immune system has to work very hard to control these infections and this ?diverts? them away from new infections such as flu.
We propose to use anti-viral drugs, that are often used to treat diseases such as cold sores, to dampen down CMV and therefore allow the immune system to recover from fighting the virus. We anticipate that the efficiency of the immune response will then improve and make a stronger response to flu vaccination.
In the first part of the study we will find the dose of tablet that is most effective in this effect and see how long it needs to be taken for. In a second section we will use this dose in a large cohort of elderly donors who are receiving their influenza vaccine. We will therefore test if this intervention is effective.
If proven, this form of treatment could be valuable in a wide range of clinical conditions and help to promote healthy ageing.

Technical Summary

Influenza remains a global health concern and the recent emergence of H1N1 ?swine flu? has increased the potential for a new pandemic. Advances in viral genomics allow new viral strains to be sequenced rapidly and appropriate vaccine production may potentially be accomplished before seasonal epidemics. However, many individuals fail to achieve a protective immune response to vaccination and this problem is seen commonly in elderly individuals in whom influenza-associated morbidity and mortality is most marked.
Cytomegalovirus (CMV) is a herpesvirus that infects the majority of the UK population and, like all viruses in this group, is never cleared from the host. The cellular immune response against CMV is critical in preventing viral reactivation but accumulates within the host such that it can represent over 10% of the total T cell pool. This impairs the host response to other infections and epidemiological studies have shown that CMV infection is associated with the development of immune senescence, ?frailty? and impaired immune response to influenza vaccination.
In this proposal we present a Developmental Clinical Study in which we will utilise drugs used commonly in the treatment of herpes simplex virus infections to reduce the frequency of subclinical CMV reactivation in elderly individuals. Uniquely, the primary aim of this approach will be to suppress the CMV-specific T cell immune response and therefore improve in vivo immune function. In the first phase of the study we will determine the dose, treatment duration and efficacy of therapy with valacyclovir for suppression of the CMV-specific immune response. Once this information has been established the second phase will be a randomised phase II study of valacyclovir in elderly individuals in order to determine if treatment can lead to an improvement in the immune response to the annual influenza vaccination.
This study is appropriate for the MRC DCS scheme as it represents a second line novel indication for a current medication and tackles a major clinical concern for UK health as well as contributing to the MRC strategic aim to promote healthy ageing. The proposal has developed from basic research into the immune response to herpesvirus infection and could have major implications for the management of immune dysfunction in the elderly.

Publications

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Cowley NJ (2017) Cytomegalovirus in Patients in the Intensive Care Unit-Reply. in JAMA internal medicine

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Firth C (2016) Cytomegalovirus infection is associated with an increase in systolic blood pressure in older individuals. in QJM : monthly journal of the Association of Physicians

 
Title Valaciclovir 
Description The grant is funding the first clinical trial of valaciclovir in healthy elderly donors. We are seeking to understand if the drug is able to improve health and immune function through the suppression of chronic herpesvirus infection. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Impact Trial is currently in progress and assessment of outcome will follow