The effects of vaccination and immunity on bacterial infection dynamics in vivo: a systems biology analysis

Lead Research Organisation: University of Cambridge
Department Name: Veterinary Medicine

Abstract

Salmonella enterica causes severe diseases such as typhoid fever, gastroenteritis and septicaemia in humans and in many animal species world-wide. Fatal disease in domestic animals results in severe economic losses; the bacteria can also persist undetected in food animals causing very serious problems to the food industry due to the high incidence of food poisoning. So far it has been difficult to control Salmonella infections using hygiene and biosecurity measures and an increasing number of salmonellae are becoming resistant to numerous drugs. Some of the currently used vaccines against S. enterica, that have been generated mainly though empirical research, confer a moderate, albeit suboptimal, level of protection against colonisation and/or disease. Recent advances in immunology and bacterial genetics offer the possibility to improve vaccine design and delivery, and this process would be empowered by a thorough understanding of how the infection process develops in the presence of different types of immunological pressure. We propose a novel multidisciplinary approach to analyse, in vivo, how different classes of vaccines and types of immune response affect bacterial growth, death, spread and distribution (population dynamics) in the host. The work will develop through different levels of complexity spanning from the analysis of the effects of vaccines and immunity on the direct interactions between individual bacteria and host cells (focal dynamics) to the analysis of how individual molecularly tagged populations of bacteria spread and grow into and between different organs (global dynamics). The interactions between bacteria and cells at the level of individual infection foci (focal dynamics) will be captured by advanced microscopy techniques that allow the observation of fluorescent S. enterica in cells and tissues. The global dynamics of the infection will be studied by monitoring the numerical and spatial fluctuations of distinct bacterial subpopulations each carrying individual DNA tags ('molecular labels') in their genome. This biological research will be integrated with the predictive and resolving power of mathematical models in a series of iterative processes whereby biology and mathematics will synergise and inform each other for a truly advanced understanding of the infection process. The novelty of the biological and mathematical approaches that we shall use is in the unraveling of the infection scenarios across different scales (systems biology research). This will lead to the analysis and reconstruction of the infection processes from their individual biological elements and to the creation of a new paradigm for the study of within-host dynamics of infection that will be extendable to a broad range of pathogens in many animal species and in humans.

Technical Summary

Salmonella infections are a serious medical and veterinary problem worldwide and a significant issue for the food industry. Control of Salmonella infections using hygiene and biosecurity measures is difficult; many antibiotics are failing due to the emergence of multi-drug resistant isolates. Current vaccines are far from optimal; design and testing of new preparations is performed empirically often based on reductionist research. The aim of the proposed research is to use a coherent systems biology approach, that evolves from our recent work, to understand how immunity and vaccines affect bacterial infection dynamics in vivo. We will use multidisciplinary research approaches to study the infection process at different levels of complexity in vivo, from the direct interaction between bacteria and host cells to the analysis of global heterogeneous traits of bacterial population dynamics in the host. Using multicolour fluorescence microscopy techniques and quantitation of molecularly tagged bacterial subpopulations we will unravel how the bacteria grow, spread, distribute and persist in the face of different types of vaccine and immune responses. Iterative feedbacks between biological work in vivo and a range of mathematical models will allow synthesis across different scales and reconstruction of the system from its individual biological elements. This work, that will be extendable to a range of pathogens and animal species, will strongly impact on human and animal health through improved understanding of the priniciples underlying vaccine design and will allow academia and industry to capitalise on the increasingly large amount of information available on the genetics of bacterial virulence and on the possibility to modulate the immune system towards specific types of response using appropriate adjuvants or vaccine delivery systems.

Planned Impact

Who will benefit from the research? The research will have an immediate impact on the broad academic scientific community and those sectors of industry currently engaged in research on host pathogen relationships, vaccine development, immuno-evasion, immunity to bacterial infection and in vivo mathematical modelling and systems biology of infection processes. Scientists will rapidly benefit from the availability of knowledge and approaches that will be developed and validated during the programme of work and that can be extended to a large number of animal and microbial species. The research will be of benefit for the general public and will impact on human and animal health due to its high impact on future trends of rational vaccine development and testing. The food industry will be another significant beneficiary of the proposed research due to the need for improved vaccines to prevent colonisation of food animals with Salmonella strains that can be transmitted to humans through contaminated meat or eggs. How will they benefit from this research? The research has the potential to impact on human and animal health worldwide given the high and widespread incidence of Salmonella infections. The proposed work will represent a leap forward towards a multi-scale understanding of the strengths and pitfalls of vaccines in the light of the dynamics of the infection process. Therefore, a major impact of the proposed research is its contribution to the replacement of empirical vaccine design and testing. The work will also contribute to a safer use of currently available vaccines. In fact, conditions that predispose to infection can, in selected cases, pose danger to the use of particular classes of vaccine. By understanding precisely the spatiotemporal requirements of immune protection, and by using iterative combinations of mathematical modeling and immunological/epidemiological observations, it will be possible to predict how a specific weakness in a component of the immune response can impact on the safety and efficacy of a particular vaccine in humans and domestic animals.

Publications

10 25 50
 
Description We have combined in vivo tracking of molecularly tagged bacterial subpopulations with mathematical modelling to gain a novel insight into how different classes of vaccines and branches of the immune response protect against secondary Salmonella enterica infections of the mouse. We have found that a live Salmonella vaccine significantly reduced bacteraemia during a secondary challenge and restrained inter-organ spread of the bacteria in the systemic organs. Further, fitting mechanistic models to the data indicated that live vaccine immunisation enhanced both the bacterial killing in the very early stages of the infection and bacteriostatic control over the first day post-challenge. T-cell immunity induced by this vaccine is not necessary for the enhanced bacteriostasis but is required for subsequent bactericidal clearance of Salmonella in the blood and tissues. Conversely, a non-living vaccine while able to enhance initial blood clearance and killing of virulent secondary challenge bacteria, was unable to alter the subsequent bacterial growth rate in the systemic organs, did not prevent the resurgence of extensive bacteraemia and failed to control the spread of the bacteria in the body.
Exploitation Route This work will have important implication for the choice of vaccines to be used in systemic salmonelloses. The work illustrated that it is necessary to develop better live attenuated vaccines because there are superior to non-living preparations. The work will have an impact on the fields of vaccine development and manufacturing
Sectors Education,Healthcare,Pharmaceuticals and Medical Biotechnology,Other

 
Description The work has not had an impact beyond academia due to the seminal nature of the research. However the research has generated results that have created a framework to study how vaccines work and this will have a societal impact on healthcare worldwide
First Year Of Impact 2013
Sector Education,Other
Impact Types Societal

 
Description Bacterial pathogenesis, immunology and vaccine development. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The talk generated interest in the subject and many Brazilian students and academics have made further contacts with us

I was asked by students about the possibility of visiting my lab in the UK
Year(s) Of Engagement Activity 2015
 
Description Bayesian analysis of within-host dynamics of Salmonella enterica after single passage through mouse organs. The Fifth International Conference on Infectious Disease Dynamics 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The poster generated questions and discussion

None yet
Year(s) Of Engagement Activity 2015
 
Description Focal and global in vivo infection dynamics to understand bacterial pathogenesis, immunity and vaccines. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The talk sparked interest and critical discussion

not aware of any
Year(s) Of Engagement Activity 2013
 
Description Foreign guest speaker at the Congress of the Brazilian Society of Immunology, Sao Paulo, Brazil, 29 October - 2 November 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Foreign guest speaker at the Congress of the Brazilian Society of Immunology, Sao Paulo, Brazil, 29 October - 2 November 2016. Title of the presentation: Imaging, omics, and immunology to understand the pathogenesis, prevention and treatment of invasive bacterial infections. The talk increased awareness on the need for multidisciplinary in designing rational treatments and prevention strategies for bacterial infections
Year(s) Of Engagement Activity 2016
 
Description Immunity to invasive Salmonella infections: should lessons from mice and man inform vaccine development? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The visit to Malawi and the talk sparked a large collaborative Grant application to the Wellcome Trust

After my talk several colleagues expressed the wish to integrate their epidemiological research with immunological studies in humans in Malawi
Year(s) Of Engagement Activity 2015
 
Description Integration of biology and mathematical modelling towards a better understanding of pathogen behaviour and rational design of improved bacterial vaccines. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk sparked discussions and research contacts

none yet
Year(s) Of Engagement Activity 2015
 
Description Keynote speaker at the 2nd World Congress on Antibiotics and Antibiotic Resistance, Manchester, UK, 13-15 October 2016. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote speaker at the 2nd World Congress on Antibiotics and Antibiotic Resistance, Manchester, UK, 13-15 October 2016. Title of the presentation: Relationships between pathogen behavior, immunity and efficacy of antimicrobial drugs within a mammalian host. The talk generated interest in the relationships between in vivo behaviour of bacteria and out use of vaccines and antimicrobials. The talk increased awareness that we must take care of the characteristics of the infection before designing treatment and prevention strategies
Year(s) Of Engagement Activity 2016
 
Description New approaches for the rational design of safer live attenuated bacterial vaccines. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Increased awareness to have safer live vaccines for endemic areas

None yet
Year(s) Of Engagement Activity 2015
 
Description Talk at Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote speaker at the 3rd Euro-Global conference on Infectious Disease, Frankfurt, Germany, 5-7 September 2016. Title of the presentation: Immunity, vaccination, antimicrobial treatment and in vivo pathogen behaviour: from the laboratory to clinical setting in endemic regions. Increased awareness on linking fundamental vaccinology with the needs in clinical settings
Year(s) Of Engagement Activity 2016
 
Description The importance of understanding bacterial spread in the tissues in relation to the host inflammatory response for the generation of safer and less reactogenic vaccines. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The talk made postgraduate and undergraduate students aware of the importance of tailoring vaccines to the specific biological characteristics of the pathogen

Several students asked for my papers and reviews on the subject and expressed an interest in undertaking research on vaccines and immunity
Year(s) Of Engagement Activity 2013
 
Description The interaction between Salmonella and host immunity at the level of cells, organs and systems. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The talk sparked interest in our research approaches and instigated collaborative research

After my talk, an application for a PhD studentship was submitted jointly with my colleague in Newcastle. This application was successful.
Year(s) Of Engagement Activity 2014
 
Description Title of the presentation: Pathogen behavior and host immunity at the level of cells, organs and systems. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Collaborative research

After my talk, collaborative research was started with the Biozentrum in Basel
Year(s) Of Engagement Activity 2014
 
Description Why live vaccines may be most effective for preventing Salmonella infections 
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 The press release will engage media and general public with our research


Just issues. Impact will be monitored over the next few months
Year(s) Of Engagement Activity 2014
URL http://www.cam.ac.uk/research/news/why-live-vaccines-may-be-most-effective-for-preventing-salmonella...
 
Description Within host infection dynamics in bacterial immunology and vaccine development. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact The activity generated a more informed assessment of vaccine strategies for invasive salmonelloses and also generated discussion between people involved in decisions on the selection of vaccine candidates.

Impacts on rationale choice of vaccine candidates
Year(s) Of Engagement Activity 2013
 
Description Within host infection dynamics in bacterial immunology and vaccine development. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Research Seminar. Novartis Institute for Vaccine Research, Siena, Italy. 19 March 2013.

no actual impacts realised to date
Year(s) Of Engagement Activity 2013
URL http://www.axonology.com/meninwhite.html