Combined use of novel diagnostoc tools and strategic vaccination to control bovin brucellosis in endemic areas

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Epidemiology and Population Health

Abstract

Brucellosis is an infectious disease of animals that also affects people (a zoonosis). It is one of the most common zoonoses worldwide and it imposes a vast burden on livelihoods as a result of human disease and impaired livestock productivity as infected animals can experience infertility, abortions and low milk yield. However, brucellosis is rarely prioritized by health systems and as a result the World Health Organization (WHO) includes it as one of its seven neglected endemic zoonoses. Although Great Britain is free from Brucellosis a constant effort is needed to ensure that cattle and sheep remain free from the disease and to be able to detect it as soon as possible in the event of its introduction. More than a million tests per year are conducted for that purpose in GB. In India brucellosis is endemic and recent reports suggest its incidence may be increasing. In this project UK-based and India-based scientists will work together in an area (Punjab) where Brucellosis is endemic among cattle and buffalo. Control of ruminant brucellosis has been achieved with different degrees of success in several settings by applying a range of diagnostic and vaccines. Previous work carried out by the research team suggests that control programs based on targeted, strategic vaccination of some groups of animals may be a cost-effective way of significantly reducing the prevalence in endemic areas wen resources are limited and animal movement between infected and non-infected herds cannot be fully avoided. However, although vaccines are effective at protecting animals from infection and reducing the prevalence of disease in the long term, an important problem of the use of vaccination is the inability to differentiate between truly infected and vaccinated animals with conventional diagnostic tests. In this project our aim is to carry out a detailed study of the epidemiology of brucellosis in bovines and humans in Punjab, including the use of novel diagnostic tests that can differentiate between vaccinated and infected animals. We will use the results to create computer models that we could use to simulate the effect of a control strategy that incorporates the use of these tests. The project will also study the economic impact of the infection, so that we can propose to the veterinary and public health services a control strategy that is realistic and truly benefits local livestock keepers and the population as a whole. The lessons that we will learn with regard to the laboratory testing of infected animals may eventually benefit countries that are free from the disease, such as GB, but have to spend considerable resources in testing animals to ensure that they remain free from infection.

Technical Summary

Brucellosis imposes a vast burden on livelihoods as a result of human disease and impaired livestock productivity. Studies carried out by Guru Angad Dev Veterinary and Animal Sciences University have found seroprevalences of human brucellosis higher than 20% in selected populations in Punjab and show the need for integrated control of the disease. Control of ruminant brucellosis has been achieved with different degrees of success by applying a range of diagnostic and prophylactic tools. Researchers from The Royal Veterinary College have shown the potential impact of sustained and strategic use of existing vaccines in endemic settings and how critical it is to adapt the strategy to the level of infection and extent of animal movement. A limiting factor of vaccine-based control programs is the inability of standard diagnostic tools to differentiate between antibodies acquired as a result of natural infection or vaccination. In the proposed research we combine a detailed epidemiological study of bovine brucellosis in Punjab-including validation of novel diagnostic techniques with simulation modelling to generate evidence based on which sustainable control programs for bovine brucellosis could be designed. We will also assess incidence of human infection and economic impact of the disease through animal health economics and transactional cost economics. The results of the field studies will be used to parameterize disease transmission models and to simulate, in silico, the potential impact of different types of vaccination strategies on prevalence reduction. Field studies will also be used to evaluate conventional and novel diagnostics. Specifically, we will study a novel diagnostic strategy using assays measuring response to rLPS antigen. Overall, our work will provide evidence to inform the design and implementation of realistic and sustainable strategies for the reduction of the prevalence of bovine brucellosis and, as a result, human brucellosis, in endemic areas.

Planned Impact

the project would allow GADVASU to build capacity in epidemiology,
identified as a priority area in preparatory work leading to this call. It will also
build up local diagnostic capacity for brucellosis to international standards.
Furthermore, successful completion of the project would provide the basis for
improved control of a major livestock disease that is endemic in Punjab
seriously impacting public health and compromising livestock productivity

Publications

10 25 50
 
Description Based on a final analysis of the total sample size of 1801 at the end of this study an estimated 2.24% (95% CI: 1.61-3.11) of the rural population in Ludhiana district (Punjab) have serological evidence of past infection with Brucella
Seropositivity is more common amongst adults than children. Gender is not strongly associated with seropositivity in Ludhiana.
A small proportion of people have direct contact with cattle, but a majority report using their own milk. Nearly all report boiling milk before consuming.
Assisting with abortion appears to be strongly associated with brucellosis, but explained a low proportion of the total seropositives. Based on mathematical models of the age specifc prevalence data in humans, the risk of brucellosis infection in the general rural population was nearly 2 per 1000 per year. This is a preventable risk by efficient provision and use of cattle vaccination.
Exploitation Route The work is informing the development of diagnostic and treatment guidelines for humans as noted earlier. It will also inform information educaiton and communication messages to rural populations. A full analysis together with assessing incidence based on age specific seroprevalence provides an estimate of the burden of disease in humans. The results will be fed into the Expert Committee for brucellosis control in India. This evidence together with the evidence of the burden and effect on milk production will inform a review of the benefits compared to the costs of animal vaccination.
Sectors Agriculture, Food and Drink,Communities and Social Services/Policy,Healthcare

 
Description The work has been communicated to the state epidemiologist of the public health department in the Punjab. The interest and contribution by this colleague has helped facilitate permissions for the conduct of the field work at the primary health care and village level, increased partnership and communication with the collaborating academic institution in India (Post Graduate Institute of Medical Education and Research, Chandigarh) and more importantly highlighted possible new ways to reduce disease burden from brucella in humans by animal vaccination ie working with veterinary services and veterinary and agricultural academic institutions in the Punjab. A greater readiness to consider the research output for policy has been created. In January 2017 draft diagnostic and treatment guidelines for brucellosis in humans were developed with our collaborators at the Post Graduate Institute of Medical Education and Research in Chandigarh. A half day meeting to discuss them was convened. The meeting includes senior epidemiologists, medical and veterinary microbiologists, internal medicine and occupational medical specialists and state level public health officials. The aims include formalising the guidelines, developing an action plan to cascade them down to primary health care settings in the State and liaise with relevant partners at the national level to assess the appropriateness of further refinement a development into national guidelines. A set of guidelines exist in India for Leptospirosis which acts as a template. Interest was also generated in ongoing surveillance of clinical brucella cases diagnosed in hospital which can be used for further research but more importantly to assess interventions to control human brucellosis eg animal vaccination, effective training for personal protective measures during high risk activities such as calving and separate areas away from village houses for calving. Results have been shared with the Punjab State Department for Public Health who are extremely interested in these findings and very engaged with the project. In addition, we have provided them with the protocols for fieldwork so that other research groups planning to conduct surveys of brucellosis in other districts can use a standardised protocol to obtain results that are comparable.
First Year Of Impact 2017
Sector Healthcare
Impact Types Policy & public services

 
Description Clinical guidelines for management of human brucellosis in Punjab
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact The increased awareness of the disease in clinical practice and the production of guidelines will help reduce morbidity from a bacterial illness which can produce disabling symptoms and loss of ability to carry out activities due to chronic fevers and lower back pain.
 
Title Questionnaire to assess main modes transmission of brucella in humans in India using electronic data capture (Open Data Kit) 
Description A standardised closed ended questionnaire to assess main exposures to brucella at the household and individual level together with standard operating procedures for recruitment, consent, blood and data collection. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2016 
Provided To Others? Yes  
Impact This tool is being used in similar studies in West Africa and in another study in Jordan (on MerscoV) and will be made available at appropriate opportunities to other researchers 
 
Title mathematical model to estimate incidence of brucella infection in humans based on serological data 
Description A deterministic compartmental model was designed to estimate the force of infection based on age specific serological data. It is more complex when events are sparse as in this case unlike similar models to estimate the incidence of malaria. The work is novel and obviates the need for arduous longtudinal studies of disease incidence where active ascertainment and repeated testing is required. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2018 
Provided To Others? Yes  
Impact No impacts can be reported yet . The anticipated impact will be to allow more rapid assessment of need for control measures and assessing effectiveness of interventions 
 
Title Mathematical model of Brucella transmission within a herd in rural Northern India 
Description Disease transmission models of brucellosis developed by the RVC are now being parameterized with data from this study. The model is a within-herd Susceptible-Exposed-Infectious-Recovered-Susceptible (SEIRS) model with an additional compartment for persistently infected (PI) and vaccinated (V) individuals (Fig 4). The model is based on differential-equations and is age-structured. The best-fit transmission parameter was obtained using data from previous RVC field studies1. The model was used to investigate the effect of the increased age of Indian cattle on the spread of brucellosis upon introduction to an organised Punjabi dairy farm (compared to other settings where cattle are usually culled at around 4.5 years). In addition, the potential impact of vaccination under different scenarios (varying effectiveness, herd size & transmission coefficients) was investigated. 
Type Of Material Computer model/algorithm 
Provided To Others? No  
Impact There are no impacts yet but the database will be used to perform risk factor analysis and modelling of transmission of the disease from livestock to humans. This can eventually inform best strategies for control of brucellosis, a zoonotic infection assumed to be responsible for considerable economic and public health burden. A poster presentation of the model at the International Brucella Conference won the best poster prize. H. R. Holt, W. A. Beauvais, P. Kaur, J.S. Bedi, N.S. Sharma, R. Kumar, J.P.S. Gill, M. Kaur, P. Mangtani & J. Guitian. Development of disease transmission models for bovine brucellosis in India. Brucellosis 2016 International Research conference, Nov 2016. 
URL http://www.dbtbrucellosis.in/brucellosis2016/invitation.php
 
Description Public Health dept at the Indian State level 
Organisation State Public Health Department, Punjab, India.
Country India 
Sector Public 
PI Contribution Expertise in assessing brucella epidemiology and means of protection in humans.
Collaborator Contribution Insights into methods to monitor disease and an understanding of the public health activities in the state for the control of zoonoses and other emerging infectious disease. This information provided some context into whcih moer nuanced options for the surveillance and control of diseases may be possible.
Impact contributions to the cllinical guidelines for the testing and treatment of brucellosis in humans.
Start Year 2016
 
Description Social Science expertise 
Organisation Post Graduate Institute of Medical Education and Research (PGIMER)
Country India 
Sector Academic/University 
PI Contribution I explored with a senior social science researcher in India the prooposed research. She became interested in and provided active research time pro-bono to support the assessment of the governance of brucella control and vaccination in Punjab.
Collaborator Contribution The researcher has been key in conducting and supervising qualitative interviews and focus groups and is also synthesising the evidence for publication. The researcher has also actively informed the information and ways to impart to subjects the problem and the means to keep safe.
Impact An oral presentation at the internal Brucella conference in Novemeber 2016
Start Year 2015
 
Description International brucellosis conference, Delhi, Nov 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Preliminary project results were disseminated at this meeting, which brings together Brucella experts from all over the world. The meeting also contained several discussions on the sustainable control of the disease in India. The PI for this project (J. Guitian) gave a keynote speech and chaired a panel discussion on the control of brucellosis. Further to this the following presentations directly linked to this project were given:

Oral presentations:

P. Kaur, H. R. Holt, N. S Sharma, J.S Bedi, J. McGiven, A. K Arora, M. Chandra, J P S Gill and J. Guitian. Sero-prevalence studies on brucellosis in cattle and buffaloes in Ludhiana district of Punjab, India. Brucellosis 2016 International Research conference, Nov 2016.

M. Kaur, P. Allen, H. R. Holt, P. Mangtani, S. Bharati, V. Sagar, A. Kulashri, J. Guitian and R. Kumar. Brucellosis Prevention & Control: Institutional Barriers & Facilitators. Brucellosis 2016 International Research conference, Nov 2016.

P. Mangtani, W. Beauvais, H. Holt, A. Kulashri, S. Bharti, V. Sagar, J.S Bedi, M. Kaur, J. Guitian, G.S Grover and R. Kumar. Sero-prevalence and risk factors for human brucellosis in Ludhiana district in Punjab, India Brucellosis 2016 International Research conference, Nov 2016.

Poster presentations:

J.S Bedi, H. R. Holt, J.P.S. Gill, Paviter Kaur, Prabhdeep Kaur, N.S. Sharma, J. Guitian and P. Mangtani. Epidemiology of Brucellosis in an Occupationally Exposed Group in Punjab, India. Brucellosis 2016 International Research conference, Nov 2016.

H. R. Holt, W. A. Beauvais,, P. Kaur, J.S. Bedi, N.S. Sharma, R. Kumar, J.P.S. Gill, M. Kaur, P. Mangtani & J. Guitian. Development of disease transmission models for bovine brucellosis in India. Brucellosis 2016 International Research conference, Nov 2016. (Won 1st place poster price).

Key persons involved with brucellosis control (both India- and world-wide) are now aware of the project. Such a strong presence in this high profile event was a great platform to give visibility to the project, share some of the findings with the international research community and discuss the practical implications of our preliminary results for the future of brucellosis control in India. After the conference, a number of researchers from India and elsewhere have been in contact with the research team to discuss possible collaborations and request assistance mostly for the design of epidemiological studies and the analysis of epidemiological data.
Year(s) Of Engagement Activity 2016
URL http://www.dbtbrucellosis.in/brucellosis2016/invitation.php
 
Description Stakeholder workshop - brucellosis control Nov 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact A workshop between State-level livestock, public health and food-safety stakeholders was organised around the theme of brucellosis control. The workshop was held in Chandigarh, Punjab, India on the 21st November 2016. The main objectives of the workshop were to ascertain what is being done to control brucellosis in Punjab, identify opportunities to improve control and share project results with stakeholders. Nineteen participants attended the meeting, representing the main institutions involved in zoonosis control in Punjab, including Departments of Animal Husbandry, Dairy Development and Health and the Food and Drug Administration. In addition, public and animal health researchers, clinicians and representatives from the private sector (cooperatives and milk union) were present. The workshop covered three themes (current efforts to control the disease, barriers to the control of the disease and mapping solutions to identified barriers). All of which are used to form future recommendations of the project.

Engagement with these partners has allowed barriers currently precluding the control of the disease to be identified which will inform the modelling component of the project. It has also opened up a channel of communication for dissemination of results to relevant stakeholders.

Attendees of the meeting were in addition keen to participate in future activity. They further suggested technical expert group should be formed to develop State-level, and maybe even countrywide, guidelines for the diagnosis of brucellosis and management of cases (both human and animal). This group should also facilitate inter-sectoral communication on action to improve and deliver control measures. This was followed up in a later meeting around best practice guidelines for diagnosis and treatment in humans.
Year(s) Of Engagement Activity 2016