Top Jabs - Improving vaccination responses in older adults
Lead Research Organisation:
University of Birmingham
Department Name: Immunity and Infection
Abstract
Older adults are more likely to get infections than young people, which is why the NHS vaccinates against the ?flu and pneumonia because of immune system ageing. Unfortunately, as people age, their body?s immune system works less well, meaning that responses to vaccination are less able to protect against illness. It is important to better understand why older people have poorer vaccine responses and to improve these. We plan to research this in older animals and humans. We will look at the processes involved in making high quality antibodies in mice, and test three ways of improving the vaccination response in mice and humans ? adding to vaccine components; improving people?s sensitivity to insulin; or simply changing the time of day when vaccines are given.
Technical Summary
Older adults are more susceptible to bacterial and viral infections than young people and the national vaccination programmes against influenza and Streptococcus pneumonia are the primary preventive measure aimed at reducing incidence of these infections. However, the decline in immune function in old age reduces the ability of older individuals to mount successful vaccination responses, with less than half of over 65 year olds producing a protective response to influenza. With age both the quantity and quality of antibody produced is reduced, which will reduce the efficacy of vaccination in older adults. Many older adults are therefore not benefitting from the protection provided by vaccination. There is an urgent need to understand why the vaccination response is compromised in old age and to develop interventions to improve vaccination responses in elders.
We plan to address several aspects of the immune response to vaccination in older animals and humans to determine why there is a failure to develop good humoral immune responses in older adults. T cell memory and B cell differentiation are directed by adult lymphoid tissue inducer (LTi) cells. We will test if and how their reduced function impacts on reduced antibody responses in old age. In addition, immune complexes have been used as adjuvants in old mice, and we will study how antigen-masking changes selection and affinity maturation of B lymphocytes in lymphoid tissues in older animals. Crucially, we will test whether antigen-masking can be used as an efficient and novel vaccine adjuvant in older animals.
Age related hormonal and metabolic changes also contribute to reduced immune responses. The study will test whether insulin sensitivity is related to vaccination responses, and will test in a small pilot study in animals whether a pharmacological intervention (metformin treatment) can improve vaccine response. Finally, a simple behavioural intervention will be used to modulate efficiency of vaccination responses: Our preliminary data show that diurnal variations in older adults lead to changes in the quality of humoral vaccine responses. We will repeat this in a larger randomised trial and test whether diurnal changes in responsiveness are due to variations in stress hormones or cytokines. If proved effective, this observation will lead to a simple intervention by manipulating the timing of immunization to improve the response to vaccination in older adults.
We plan to address several aspects of the immune response to vaccination in older animals and humans to determine why there is a failure to develop good humoral immune responses in older adults. T cell memory and B cell differentiation are directed by adult lymphoid tissue inducer (LTi) cells. We will test if and how their reduced function impacts on reduced antibody responses in old age. In addition, immune complexes have been used as adjuvants in old mice, and we will study how antigen-masking changes selection and affinity maturation of B lymphocytes in lymphoid tissues in older animals. Crucially, we will test whether antigen-masking can be used as an efficient and novel vaccine adjuvant in older animals.
Age related hormonal and metabolic changes also contribute to reduced immune responses. The study will test whether insulin sensitivity is related to vaccination responses, and will test in a small pilot study in animals whether a pharmacological intervention (metformin treatment) can improve vaccine response. Finally, a simple behavioural intervention will be used to modulate efficiency of vaccination responses: Our preliminary data show that diurnal variations in older adults lead to changes in the quality of humoral vaccine responses. We will repeat this in a larger randomised trial and test whether diurnal changes in responsiveness are due to variations in stress hormones or cytokines. If proved effective, this observation will lead to a simple intervention by manipulating the timing of immunization to improve the response to vaccination in older adults.
Publications

Cox L
(2014)
The new science of ageing

Arber S
(2014)
The new science of ageing

Phillips AC
(2012)
The vaccination model in psychoneuroimmunology research: a review.
in Methods in molecular biology (Clifton, N.J.)

Ross EA
(2012)
Thymic function is maintained during Salmonella-induced atrophy and recovery.
in Journal of immunology (Baltimore, Md. : 1950)

Brown G
(2015)
Versatility of stem and progenitor cells and the instructive actions of cytokines on hematopoiesis.
in Critical reviews in clinical laboratory sciences

Toellner KM
(2018)
What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? A Role for Antibody Feedback.
in Cold Spring Harbor perspectives in biology
Description | AgeWell annual research days |
Amount | £15,000 (GBP) |
Organisation | University of Birmingham |
Department | Medawar Centre for Healthy Ageing Research |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2011 |
End | 10/2013 |
Description | AgeWell annual research days continued |
Amount | £15,000 (GBP) |
Organisation | Versus Arthritis |
Department | Arthritis Research UK Centre for Musculoskeletal Ageing Research |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2014 |
End | 10/2017 |
Description | Biomedical Vacation Scholarships |
Amount | £1,080 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2013 |
End | 06/2013 |
Description | Determining the potential universal applicability of a diurnal response to vaccination and the associated circadian immune processes |
Amount | £550,130 (GBP) |
Funding ID | MR/P001874/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2017 |
End | 12/2019 |
Description | Horizon 2020 Marie Curie Multi-site International Training Network |
Amount | € 2,873,941 (EUR) |
Funding ID | [675003] |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 01/2016 |
End | 12/2020 |
Description | MRC Centenary award |
Amount | £5,900 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2012 |
End | 04/2013 |
Description | MRC Centenary award |
Amount | £8,655 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2012 |
End | 04/2013 |
Description | MRC Centres Capital Awards |
Amount | £254,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2013 |
End | 04/2014 |
Description | MRC Confidence in Concept, Design and preclinical testing of a cancer specific vaccine |
Amount | £67,212 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2013 |
End | 04/2014 |
Description | MRC DPFS, Specific targeting of a pro-inflammatory B cell subset in rheumatoid arthritis |
Amount | £591,471 (GBP) |
Funding ID | MR/M007669/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2014 |
End | 06/2017 |
Description | Project grant Effects of IL-22 deficiency on germinal centre physiology |
Amount | $437,000 (USD) |
Organisation | Pfizer Inc |
Sector | Private |
Country | United States |
Start | 11/2011 |
End | 11/2013 |
Description | Project grant How does systemic flagellin immunization induce mucosal IgA |
Amount | £654,061 (GBP) |
Funding ID | BB/L009986/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2014 |
End | 03/2017 |
Description | Public Involvement Fund for patient participant involvement in planned NIHR funded clinical trial |
Amount | £350 (GBP) |
Organisation | Research Design Service, West Midlands |
Sector | Public |
Country | United Kingdom |
Start | 01/2016 |
End | 07/2016 |
Title | monoclonal antibody NP-specific |
Description | Several hybridomas producing monoclonal antibodies with defined specificities to 4-hydroxynitrophenyl (NP) have been made, which can be used to study regulation of antibody responses to NP. |
Type Of Material | Antibody |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | These tools allow study of antibody feedback in the regulation of B cell selection in germinal centres |
Description | Gene expression in memory B cells |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provision of mRNA from in vivo differentiated memory B cells |
Collaborator Contribution | Gene expression analysis from different in vivo differentiated memory B cells by RNAseq and bioinformatic analysis |
Impact | New data on gene expression in new memory B cell subsets. |
Start Year | 2015 |
Description | In silico modelling of germinal centres |
Organisation | Helmholtz Association of German Research Centres |
Department | Helmholtz Centre for Infection Research (HZI) |
Country | Germany |
Sector | Academic/University |
PI Contribution | Data provision for in silico models Work on the in silico model |
Collaborator Contribution | In silico modelling Predictions for optimal experimental in vivo setups |
Impact | The collaboration has led to several publications. It has produced a new in silico model to analyse the regulation of affinity maturation in germinal centres. This has lead to several further collaborations and publications for our collaborators. |
Start Year | 2006 |
Description | Intravital imaging of memory B cell migration |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provision of GMO mice, |
Collaborator Contribution | Immunisation of GMO mice and intravital imaging of migrating memory B cells. Training visits for UoB staff on intravital microscopy in preparation. |
Impact | Early results show new patterns of memory B cell migration and roles of chemokine receptors directing this. |
Start Year | 2016 |
Description | Intravital imaging of plasma cell differentiation |
Organisation | Leibniz Association |
Department | German Rheumatism Research Centre |
Country | Germany |
Sector | Charity/Non Profit |
PI Contribution | A postdoctoral research fellow spent twice 2 months at DRFZ to learn intravital imaging techniques and study plasma cell differentiation from germinal centres |
Collaborator Contribution | Hosting, training, and help with experiments. Provision of experimental animals |
Impact | Training of postdoctoral research fellow Preliminary data on plasma cell differentiation Submission of funding proposal to Wellcome Trust for an intravital microscope |
Start Year | 2011 |
Title | CONJUGATED VACCINE |
Description | The present invention provides a composition for provoking an immune response in a patient to an autoantigen target, the composition comprising the target conjugated a carrier polypeptide. |
IP Reference | US2016136287 |
Protection | Patent granted |
Year Protection Granted | 2016 |
Licensed | No |
Impact | None yet |
Title | Tumour endothelium targeting B cell vaccine |
Description | We have developed a vaccine that induces antibody to tumour vessel expressed antigens, inhibiting tumour growth. This has been tested and developed in mice. Translation to a human version has started. At the moment further funding is sought. Last source of funding was MRC CiC. |
Type | Therapeutic Intervention - Vaccines |
Current Stage Of Development | Refinement. Non-clinical |
Year Development Stage Completed | 2014 |
Development Status | Actively seeking support |
Impact | The vaccine design should be applicable for other targets, e.g. other tumour expressed antigens, or other autoantigens involved in the pathogenesis of other diseases. |
Description | Interactive presentation and poster at Lifelong Health and Wellbeing Public Showcase, |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | About 150 members of the public attended this interactive display and discussion session Many questions were asked about how to boost immunity |
Year(s) Of Engagement Activity | 2012 |
Description | Invited talk and display for NDA and LLHW joint Public Engagement Event |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | 100 older adults and practitioners attended the talks and interactive presentation which sparked questions and discussion The public asked about the best time to have vaccinations for best immune protection |
Year(s) Of Engagement Activity | 2013 |
Description | Levels of antibodies in saliva are associated with risk of mortality. |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Levels of antibodies in saliva are associated with risk of mortality. Media engagement, e.g., the Times, Daily Mail, Huffington Post, Science Daily etc. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.sciencedaily.com/releases/2015/12/151223221330.htm |
Description | Loneliness and isolation, can it affect your immunity? |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Policymakers/politicians |
Results and Impact | Loneliness and isolation, can it affect your immunity? Speaker at Dudley Age Alliance - Public engagement for older adults and practitioner, charities and health care providers |
Year(s) Of Engagement Activity | 2015 |
Description | Loneliness and isolation, can it affect your immunity? Speaker at Dudley Age Alliance |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Loneliness and isolation, can it affect your immunity? Speaker at Dudley Age Alliance - Public engagement for older adults. Invited by a member of the Birmingham 1000 elders cohort which was revamped at the original AgeWell meeting funded by this grant. |
Year(s) Of Engagement Activity | 2015 |
Description | Morning vaccination is better for older adults. |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Morning vaccination is better for older adults. Radio and TV Interviews for Naked Scientist and BBC World News, plus lots of other media nationally and globally e.g. the Guardian, NY Times, BBC Health, the Telegraph, Reuters, Huffington Post, Radio WM, O Globo, Times of India |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.birmingham.ac.uk/news/latest/2016/04/vaccinations-more-effective-in-the-morning.aspx |
Description | Museum activity day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Workshop Facilitator |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Visitors to Birmingham's science museum (ThinkTank) could meet scientists and learn about the immune system. Hundreds of children and their parents talked to us and engaged in activities. Children learnt about the immune system, and had a chance to meet scientists. Many were very enthused about science and experiments. We were invited back for this year and intend to return next year. |
Year(s) Of Engagement Activity | 2012,2013 |
Description | Poster and interactive display at the Lifelong Health and Wellbeing Showcase event |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | 100 members of the public attended an interactive poster session on ageing research at which we presented our work Many members of the public asked about when the best time was for their influenza vaccination |
Year(s) Of Engagement Activity | 2013 |
Description | School visits |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Workshop Facilitator |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | We ran experiments with the whole of year 6, talked about being a scientist and answered all their questions about what we did. The children learnt that they could be scientists and that not all scientists were old white men with beards and glasses! The school invited us back to talk to the children in 2014. |
Year(s) Of Engagement Activity | 2012,2013 |
Description | Speaker at Bright Club - Public engagement with Science event. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Speaker at Bright Club - Public engagement with Science event. Comedy presentation of science |
Year(s) Of Engagement Activity | 2015 |
URL | https://www.youtube.com/watch?v=bK2BNCguX8w |