Interaction between live and killed vaccines: effect of DTP combined vaccine on T cell memory after measles vaccination

Lead Research Organisation: MRC Unit, The Gambia

Abstract

Live vaccines consist of weakened live organisms, and killed vaccines consist of dead bits of organisms or toxins they produce. Vaccines work by stimulating immune responses in the form of T cells, antibodies and soluble substances called cytokines which fight against the vaccine disease if the person is exposed to it in the future. There is evidence that live vaccines (e.g. measles vaccine (MV)) and killed vaccines (e.g. combined diphtheria, tetanus, pertussis vaccine (DTP)) interact with one another. Specifically, live vaccines give beneficial effects other than protecting against the target disease, but killed vaccines cancel these beneficial effects leading to an increase in deaths. The main aim of this study is to investigate how killed vaccines alter the immune response to live vaccines. We will either give DTP with MV or give MV alone at 9 months of age, and look at the effect on the childs immunity. Understanding interactions between commonly used vaccines will ultimately lead to recommendations regarding safer practices in the future, and provide vital information for the introduction of new vaccines.

Technical Summary

The introduction of routine vaccination in infants in the form of the expanded program on immunisation (EPI) has had an enormous impact on childhood morbidity and mortality, and millions of doses of vaccines are administered each year. However, the current EPI schedules were recommended >20 years ago, and the WHO Strategic Advisory Group of Experts agree that it may be time to review the scientific evidence and revise current immunization schedules. In the developing world routine vaccines are frequently missed or administered in the wrong order, but there is increasing evidence that the order in which live and killed vaccines are administered is important. Specifically, live vaccines (e.g. measles vaccine (MV)) provide beneficial effects other than protecting against the target pathogen, whereas co-administration of killed vaccines (e.g. diphtheria, tetanus, pertussis (DTP)) seems to negate these beneficial effects leading to increased all cause mortality. Moreover, in most of these studies boys and girls seem to behave differently with survival risks / benefits favouring one sex more than the other. The aim of this proposal is to investigate the immunological basis behind these observations.||300 children have been enrolled into a prospective randomised study to either receive their EPI vaccines according to Gambian guidelines; have the third dose of DTP, which is normally given at 4 months, delayed and administered with measles vaccine at 9 months of age; or receive DTP3 alone at 9 months. Boys and girls are randomised separately for later analysis by sex. Memory responses are being tested at 4 weeks and 9 months after the 9 month vaccines to measles vaccine specific and unrelated antigens. Children will then be challenged with MV at 18 months of age in order to mimic a measles virus infection, and 4 week post challenge effector responses will be analysed.|The results will be used to identify markers that might be associated with poor outcomes for use as a practical tool for testing in field studies, including samples from an ongoing large scale randomised trial of DTP / MV interactions in Guinea Bissau. Our study will contribute to the scientific framework for recommending safe EPI practices, and may have direct effects in documenting that DTP should not be given with or after MV. The results will also inform us about potential interactions that might be applied to other vaccine combinations, which is particularly important given the number of new vaccines that are currently being developed.

Publications

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Flanagan KL (2013) Heterologous ("nonspecific") and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

 
Description Clifford Craig Medical Research Trust
Amount $20,000 (AUD)
Organisation Clifford Craig Medical Research Trust 
Sector Academic/University
Country Australia
Start 01/2013 
End 11/2013
 
Description Grant for establishing Danish Research Centers of Excellence: Research Centre for Vitamins and Vaccines (CVIVA)
Amount € 10,000,000 (EUR)
Organisation Danish National Research Foundation (DNRF) 
Sector Public
Country Denmark
Start 03/2012 
End 02/2017
 
Description NHMRC Project Grant
Amount $1,141,331 (AUD)
Funding ID APP1051228 
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 12/2012 
End 11/2016
 
Description Bandim Health Project 
Organisation Bandim Health Project (BHP)
Country Denmark 
Sector Charity/Non Profit 
PI Contribution Training of lab staff and use of labaoratory facilities in The Gambia. Critical analysis of research proposals. Joint authroship on scientific papers. New collaborative projects written.
Collaborator Contribution Intellectual input into my studies, collaborative meetings and discussions. Samples from Guinea Bissau being analysed in my lab in The Gambia, training of Guinea Bissau staff in my lab.
Impact The award of an EU grant in 2010 to study the non-specific effects of vaccines on mortality in 3 countries in West Africa. MRC Gambia will conduct immunological assays and provide immunologiucal support. The collaboration is multidisciplinary and involves clinicians, epidemiologists, statisticians and immunologists.
Start Year 2008
 
Description CVIVA 
Organisation The Statens Serum Institute (SSI)
Department Research Center for Vitamines and Vaccines
Country Denmark 
Sector Public 
PI Contribution Intellectual input into study design, co-supervision of PhD student
Collaborator Contribution Set up prospective randomised vaccine trials in Guinea-Bissau and Denmark
Impact 2 publications and 1 submitted
Start Year 2012
 
Description Curtis NHMRC Collaboration 
Organisation Royal Children's Hospital Melbourne
Country Australia 
Sector Hospitals 
PI Contribution Chief investigator on NHMRC grant to conduct a prospective BCG vaccine trial in Melbourne
Collaborator Contribution Co-CIs, study is being set up in Melbourne
Impact None
Start Year 2011
 
Description Monash Plebanski collaboration 
Organisation Monash University
Department Department of Immunology and Pathology
Country Australia 
Sector Academic/University 
PI Contribution A collaboration with Prof. Magdalena Plebanski, head of the Vaccine and Infectious Diseases Laboratory in the Dept of Immunology.
Collaborator Contribution We have 2 joint PhD students. Have recently hosted a Gambian student in the lab. Have publised 1 paper together, writing more papers and a grant.
Impact 1 publication - Clinical Immunology 2013; 149(1): 97-110
Start Year 2011
 
Description 13th NICS Meeting, 2012 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact Poster presentation of my research at the 13th National Immunization Conference in Darwin, Australia June 2012.

Further international exposure for my vaccine research
Year(s) Of Engagement Activity 2012
 
Description 7th World Congress of the World Society for Pediatric Infectious Diseases (WSPID) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact I presented a poster at the meeting

New collaborations and further international recognition for the work
Year(s) Of Engagement Activity 2011
 
Description ASID Annual Scientific Meeting 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact I gave an oral presentation at the Australasian Society for Infectious Diseases 2012 Annual Scientific Meeting held in Freemantle, Perth, Australia in March 2012

New academic contacts in Infectious Diseases in Australia
Year(s) Of Engagement Activity 2012
 
Description Sukuta Open Day 2010 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Open Day at field site where infant vaccine studies conducted. Attended by participant familes, local community, religious leaders, politicians. PI was interviewed about vaccine studies by local televison and press relase about the event was published in local newpapers.

Increased participation in ongoing studies, increased community acceptance of research activities.
Year(s) Of Engagement Activity 2010