Team:Wageningen UR/Application/Rollouttest
Rollout plan
On this page you will find the official iGEM Wageningen 2017 Rollout plan. Over the past years, iGEM teams have developed really interesting, novel and innovative diagnostics. We elaborate upon this principle by designing a plan and subsequently incorporating our human practices into it. To help future iGEM teams getting a clear overview of what needs to be taken into account when designing and implementing your diagnostic, we have developed a rollout plan in which we give a coherent summary of the steps that are taken upon the outbreak of an epidemic and where problems occur in the field. To find out about these problems, we talked to several renowned authorities with different expertises surrounding diagnostics and epidemics, and combined their insights into the following overview of how a rollout plan for novel diagnostics could and should work:
Step 1. Emergence of an Outbreak
The first signs of an epidemic are noticed. One of these signs might be an increase in the number of people showing certain symptoms in a certain area. Often, this is noticed by the local or national health centers At this point, little is known about the pathogen, vector, vector trajectory or the vulnerable target group.
The WHO recognizes a pathogenic outbreak if it fits the following definition:
A disease outbreak is the occurrence of cases of disease in excess of what would normally be expected in a defined community, geographical area or season. An outbreak may occur in a restricted geographical area, or may extend over several countries. It may last for a few days or weeks, or for several years.’ [1]
While the definition above describes the outbreak for a case where the disease in question is to be expected, there are also instances where the disease is new in that region, or re-emerges after being eradicated for some time. Therefore, the following description can fit an outbreak as well:
‘A single case of a communicable disease long absent from a population, or caused by an agent (e.g. bacterium or virus) not previously recognized in that community or area, or the emergence of a previously unknown disease, may also constitute an outbreak and should be reported and investigated.’ [1]
Dr. Marianne van der Sande
In an outbreak scenario, the priority of the people should be assessing the identity of the infectious agent. What kind of pathogen are we dealing with? What are its transmission routes? How does it cause disease?
References
- WHO, Disease outbreaks, World Health Organization, visited 18 October 2017, http://www.who.int/topics/disease_outbreaks/en/.
Step 2. Develop the diagnostic
When an official epidemic emerges, our modular device will be adapted to the new, spreading disease. Mantis can detect a pathogen itself by the antibody-like protein on its cell surface. This so-called Affibody binds an antigen of this disease, whereafter the signalling system in the cell is activated, resulting in a visible signal. During a new epidemic, the pathogen first has to be identified or isolated by officially registered laboratories. Then, via phage display our Affinity body library is screened for an Affibody which binds to this pathogen with high affinity. You can read here how this screening is performed. That’s it! A new whole-cell diagnostic test is now made. Faster than normal
Time it takes After Mantis is adapted to recognize the new pathogen, the cells for the device will be produced in a large-scale production process and shipped to the tropical area where it is needed. From there, the cell-bank with the new cells will be maintained and distributed accordingly.
Step 3. Large-scale production
After a new Mantis is made, it is produced on large scale. The production of current diagnostic tests is mostly based on enzyme purification, which is costly in resources and time consuming as well [1].
Dr. Erwan Piriou
The scale-up of the production of this whole-cell biosensors is easier than scale-up of current diagnostics
Moreover, production of current tests like dipsticks depend on a small number of companies which do not make a lot of money from this, and thus have little incentive to continue.
Prof. Joseph Ndung’u
If these companies stop the production, no alternative will be available”
Mantis can be locally grown from cell banks, and thus does not depend on single companies for the production process.
After the right affinity body is found for a rising disease, the bacterial strain is distributed to local health centres in developing countries as fast as possible. A primary health centre, like the ones located in the capital city of a country, can be a good place to set up the Master Cell Bank. From there, the cells are grown in large culturing tanks, dried and aliquoted in vials, ready for transport to more rural medical facilities. By drying the cells, they can be stably stored without the need of a cold-chain.reference.
Pascale Ondoa
Cell culturing will require a certain level of training, which is often not available in laboratories in developing countries
This means that addition of a ‘cell culturing course’ to the medical training in developing countries will thus be a necessity. This would however be a step forward in creating a self-sustaining medical structure in developing countries, and reduce the dependency of external help from developed countries.
costs?
References
- Su, Liang, et al. "Microbial biosensors: a review." Biosensors and Bioelectronics 26.5 (2011): 1788-1799.
Step 4. Getting the diagnostic to the people (Logistics)
After local production and preparation of Mantis, it has to reach the population residing in remote areas. In general, there are four basic levels of healthcare that are relevant for African OHEC (Out of Hospital Emergency Care) systems: (i) first aid, (ii) basic life support, (iii) intermediate life support, and (iv) advanced life support. Tier one providers deliver first aid, while tier two to four providers deliver basic, intermediate, and advanced life support [1]. After production and drying of the cells in the previously mentioned health centers, the diagnostic is spread throughout these tiers to the local population. During the first-time distribution of Mantis in the area, the local facilities and field teams are supplied with both the device and the whole-cell biosensor, which is directed against the disease that is most relevant at that specific time. Owing to this model, only the biosensor itself needs to be shipped in subsequent rounds (aimed against the new disease), since the device is already present on-site. A manual how to use the device will be distributed as well.
Case: Human African Trypanosomiasis HAT in Congo
In Congo, healthcare starts in local health centres (centre-de-Sante) which have staff ranging from minimally to well trained. Secondly, there are hospitals and clinics staffed by medical doctors, which often provide definitive treatment. Finally there’s a national hospital in Kinshasa. After independency of Congo from its colonizers in the 1960s, the health care system collapsed and the number of infected people increased significantly. This again points to the mayor role the western world has on these countries. Although more and more effords are taken to control epidemics in these African countries, the health system has collapsed again after recurrent political and social instability since the civil war (1997-2003). Some estimated 5 million deaths between 1997-2004 were attributable to treatable conditions.
Dr. Philippe Büscher
Although WHO issued a health system stabilization plan, the main bottlenecks in eradicating tropical diseases are still the political status of countries, due to civil wars and governmental restrictions, the availability of health care facilities, and the price for treatments
The WHO offers general guidelines for emergency assessment and treatmentreference, but Congo does not offer official guidelines. There is also no functional provincial pre-hospital care; this is a big problem as 70% of the population lives in rural areas[2].
Nowadays, institutes, mainly located in Europe, provide free screening and medication to African HAT patients. During active case detection, mobile teams travel to urban neighbourhoods or villages in rural areas to test everyone. These teams gather from a central point, e.g. local health centers, and go out with a four-wheel drive or motor bike for 20 days per month, testing around 6,000 people, depending on village sizes [3]. Mantis can be used for both passive case detection in local health centers with minimal facilities, as well as active screening by these mobile teams. Contrary to CATT, the current test that is used for HAT screening, Mantis would not require a cold-chain, as the cells are dried and stable at room temperature. As of now, only a qualitative result is given; patients with a positive result are referred to health centres for further analysis and treatment, whereas negatively tested individuals are free to go.
Case: Zika in Brazil
In Brazil, accessibility of healthcare facilities poses a smaller problem compared to Congo. Brazilian inhabitants can go to the doctor's office for free. However, these doctors do not have the expensive equipment needed to diagnose viral diseases. We learned this by talking to local Brazilian inhabitants. With Mantis, these local doctors can now diagnose patients!
References
- Mould-Millman, N. K., et al. "Assessment of emergency medical services in the Ashanti region of Ghana." Ghana medical journal 49.3 (2015): 125-135.
- WHO. World health statistics 2017. (Online) 2017. Available: http://apps.who.int/ (Accessed 18 October 2017)
- Büscher. Philippe, et al.Human African trypanosomiasis. The Lancet (2017).
Step 5. Pay the project (Funding)
The lack of financial support for programs attempting to combat neglected tropical diseases a major issue.. All aspects involved in gaining control over infectious diseases, being medical supplies, population screening or vector control measurements, are virtually impossible without the necessary funding.
Dr. Erwan Piriou
Funding for diagnostics is not centralized as is for vaccines. Due to the low-profit margins for the developers, funding can become a problem
When talking about diagnostics specifically, an additional financial hurdle is present: they have to be developed by third-party manufacturers, who often want to make profit, while keeping the price per diagnostic low and affordable. As was mentioned by MSF laboratory advisor Erwan Piriou: ‘95% of all malaria diagnostics, a tool that has proven to be extremely useful, are developed by only two companies worldwide. Since these diagnostics have to be affordable, prices have been going down for years, and so has the profit of the manufacturers.’ These manufacturers have been threatening to stop production if prices are forced down even more by the NGO’s, as they can not survive on the low profit margins.
Case: HAT in Congo
In the last decade the world's health care policy was focussed on the major diseases HIV/ AIDS, malaria and tuberculosis, resulting in allocation of the funding for the goal of controlling these diseases [1]. Relatively unknown neglected tropical diseases (NTDs), like HAT, have been overlooked in financial support, partly due to their non-changing situation and seemingly low direct impact on population. Even though these NTDs are also in great need for funding, improving their situations is often more cost-effective and has added health benefits for the local society [2].
To support the efforts of tackling smaller, lesser known diseases (like NTDs) multiple NGOs have been established, often focussing on only a few diseases at a time. They play an important role in securing funding, setting up healthcare infrastructures, communicating with governments and evoking global interest in the diseases.
Case: Zika in Brazil
Media coverage has proven to be an important factor in the attraction of funding for controlling diseases. Especially since the beginning of the 21st century, media has become more and more important. Recent outbreaks such as SARS, Ebola and Zika have gotten more attention than similar diseases have had a few decades ago.
Funding for Mantis
Funding for the Mantis diagnostic would rely on funding from global and national initiatives (e.g. World Bank, United Nations, National Institute of Health), which makes up the public-sector. Allocation of funding from such initiatives is done in consultation with the WHO and other healthcare organisations, depending on factors such as the disease burden on society and the impact of the new diagnostic [2]. The WHO monitors the global diagnostic infrastructure and decides whether a new diagnostic can and will be implemented. If it deems the Mantis diagnostic an improvement on currently available diagnostics they might, in cooperation with NGOs, allocate funding for it as well as identify potential manufacturers and implement it in the existing healthcare track.
References
- Molyneux, David H. Neglected" diseases but unrecognised successes-challenges and opportunities for infectious disease control. The Lancet. 364.9431 (2004): 380.
- Mabey, David, et al. Diagnostics for the developing world. Nature reviews. Microbiology 2.3 (2004): 231.
Step 6. Training of personnel
Case: Africa
In African regions, training capacity of medical personnel is generally insufficient [1], which results in a shortage of healthcare workers in the government-run medical system. NGO’s like Doctors Without Borders (DWB) are known to set up their own clinics and hospitals, dispersing healthcare free of charge. The hospital employs both foreign specialist and locals, in which the former educates the latter. [2] With this system of basic medical education, the Mantis device can be applied in the area by teaching the specialist the general use and mode of operation of the apparatus. The specialist in turn can instruct the local healthcare workers how to operate the device. In addition, a manual will be available to clear all uncertainty about the handling of Mantis, ensuring proper use of the device.
Case: South America
In Latin America, the degree of medical education differs greatly on multiple levels. Between countries, the contrast can already be dramatic. Mexico, for example, has advanced in developing its national standards by investing in application procedures, instruments and facilities [3]. Meanwhile, Venezuela is heavily affected by a healthcare crisis [4]. Furthermore, multiple occasions of certain institutions educating new health care workers, which lack a minimal scientific and technical level in the process have occurred, leading to large differences in the capabilities between physicians [5]. However, in most official health care institutions in the urban areas, education levels are expected to be appropriate and implementation of Mantis in the system should not pose too many problems [3]. Finally, point-of-care diagnostic tests should be operated by primary healthcare workers without any formal laboratory experience and further training with the device should not take more than 2 hours. Hurdles encountered in later situations can be solved with the supplied manual, should training still be insufficient.
FIND
Point-of-care diagnostic tests should be operated by primary healthcare workers without any formal laboratory training. Moreover, for any level health care worker, the training should be less than 2 hours
Link HAT
Link E.bola
Last visited: 18-10-17
References
- The health worker shortage in Africa: are enough physicians and nurses being trained?, Yohannes Kinfu, Mario R Dal Poz, Hugo Mercer & David B Evans (2009)
- Quote, Jeanine Loonen
- Changes, trends and challenges of medical education in Latin America, Pablo A, Pulido M, Alejandro C, Ana P, Roberto Rón P, Gloria P, Medical Teacher, Vol. 28, No. 1, 2006, pp. 24–29
- Venezuela’s health care crisis, Williams, PCM, The Lancet, Vol. 390, 2017
- Medical education based on the final competencies of the student, Páles, J, International Journal of Medical Education, Vol. 4, pp. 1
Step 7. Public education
State of Affairs
A proportional number of infections can be prevented if the local population knows how to recognize symptoms of a certain disease and what to look out for in addition. Mosquito-borne illnesses with emphasis on Zika, Dengue and Chikungunya are generally known by the locals, yet barely anyone of them was able to correctly assign symptoms to the respective disease [1]. Considering the case that these are very serious diseases (Dengue hospitalizes about 500,000 people a year, of which 12,500 die due to the consequences [2] ), this lack of insight should be closed as soon as possible.
How to Increase Awareness
Educational activities involving the relevant pathogens in the area should start as early as school begins for minors. Both public health authorities and schools should join efforts to provide a basic and coherent model of how the disease in question is affects the individual, how it spreads and what students can do to reduce their risk of infection, which should decrease the transmission rate and spread of the pathogen. The potential roles and responsibilities of school administrators will provide school districts with information for planning school-related activities for public health actions, pertaining to viral or parasitic infections. In turn, the provided information to children can be brought home by instructing the pupils to talk about the issue with their parents, which has had moderate, but effective results [1]. Child care, camp and higher educational institutions are also considered for applying this model in the future.
In conclusion, this guidance will give an overview of the potential responsibilities and roles of both schools and public health authorities regarding prevention measures that schools could implement in order to raise awareness of infectious diseases. Zika virus is a placeholder here. To reach the community, infographic tools could be implemented and used as a tool to inform students about current (Zika) concerns (Figure 1).
References
- Zika: information in the nick of time, Walker, J.L., Conway, J.H., Svenson, J.E., Viewpoints, Vol. 7 (1), p29-31, 2017
- Dengue and severe dengue factsheet, WHO website, 2017. Available: http://www.who.int/mediacentre/factsheets/fs117/en/ (retrieved 05-10-2017)
Step 8. Safety, Responsibility and Risks
Responsibility
Being manufacturers, you will not have full control on the use of your device. It could be for example disposed of incorrectly, causing damage to the environment. Or it could be used in wrong ways, such as for discriminatory reasons. It is our responsibility to avoid any misuse of the device. To that end, you can include in the label instructions on how to use it, how to dispose it and what kind of behaviours are not accepted (e.g. forcing diagnostic in case of global threat). This is something we discovered during our ethics research.
Risks
As Mantis is based on a genetically modified bacterium, it is of the utmost importance to take measures that will avoid an accidental release of the bacteria into nature. How can this be done, when the developers are not the ones using the diagnostic in the field? On one hand, the healthcare personnel will be trained to correctly dispose the vials containing the bacteria (e.g. cleaning with bleach or disinfecting with heat). On the other hand, a biocontainment mechanism will be implemented in the genetic material of the bacteria, which will prevent the uncontrolled spread of the bacteria in case of an accidental release. Besides, the risk of the bacteria affecting the environment in a detrimental way will be assessed beforehand, to determine that it fulfills the recommended standards. To learn more about biocontainment mechanisms and risk assessment, click here.
Modidi picture!! :D preferably with link
Step 9. Political impact on diagnostic availability
General
In addition to approval of global healthcare organisations such as the FDA and WHO, implementation of a new diagnostic also requires governmental approval from the country it will be implemented in. Approval is based on trial results obtained from initial testing of the diagnostic during development. The specific requirements for a diagnostic to gain approval can vary per country. Unfortunately, regulations for diagnostics to ensure product safety and effectiveness are lacking in strictness for a large amount of countries. As a result, the wrong choice for diagnostics is easily made, resulting in costly mistakes in clinical decision making [1]. Especially in developing countries these regulations are below average, because of the absence of a qualitative good healthcare system.
Case: Democratic Republic of Congo
Furthermore, unstable governmental situations can cause difficulties in the implementation of diagnostics in a country, as mentioned by Medical Entomologist Jeanine Loonen. Her work in the Democratic Republic of Congo (DRC), a country war-torn by conflicts between governmental militia and rebel groups, has taught her that negotiation with all parties is necessary. Médecins Sans Frontières has put much effort in establishing and maintaining a functioning healthcare system and infrastructure, among which is an actual medical facility providing free care. She also mentioned that the infrastructure of medical deliveries is very vulnerable in unstable areas and can easily be disrupted by arising conflicts. She experienced multiple moments where medical supplies, among which diagnostic tools, could only reach the healthcare facility by asking the local population for help, which would carry the supplies for hundreds of miles.
Similarly, previous measurements resulting in the successful control of Human African Trypanosomiasis have been undone by destabilization of central African countries such as South-Sudan. Political conflicts have resulted in abolishment of effective surveillance, diagnosis and treatment of this disease, due to breakdown of health services and lack of medical supply [2]. As a result, HAT has re-emerged in these regions from a previously controlled situation in 1960.
References
- Peeling, R. W., Smith, P. G., & Bossuyt, P. M. M. (2008). "A guide for diagnostic evaluations". Nature Reviews Microbiology, 6(11), S2–S6. http://doi.org/10.1038/nrmicro1522
- Molyneux, D. H. (2004). “Neglected” diseases but unrecognised successes: Challenges and opportunities for infectious disease control". Lancet, 364(9431), 380–383. http://doi.org/10.1016/S0140-6736(04)16728-7
Step 10. Adverse testing
Once the tests have been performed, the group tested positively for the infections will be set apart if necessary and given the option to be taken to the hospital for further testing and/or treatment. As mentioned before, the current tests (the antibody dipstick or Card Agglutination Test for Trypanosoma (CATT)) still are troubled by occasional false positives and even false negatives [1]. This means that further testing is necessary through microscopic analysis on-site (if applicable) of blood samples for HAT, or nucleic acid tests. Although the screening in field is free for the patients, hospital screening and treatment is not [2] and often require expensive investments by NGO’s. Aside from investments alone, the treatment costs can go as high as $100-200 per treatment, per patient [3].
By making a more sensitive diagnostic we aim to reduce the number of false positives, thereby also reducing research and travel expenses for the doctors and reduce healthcare costs for the patients, while still finding and helping those who need it.
References
- Demerdash, Z., Mohamed S., Hendawy, M., Rabia, I., Attia, M., Shaker, Z., Diab, T.M., Monoclonal Antibody-Based Dipstick Assay: A Reliable Field Applicable Technique for Diagnosis of Schistosoma mansoni Infection Using Human Serum and Urine Samples, Korean Journal of Parasitology, 51(1), p93-98, 2013
- Quote, Jeanine Loonen
- Quote, Philippe Büscher
Step 11. Evaluation
Diagnostic tests can be widely applied, e.g. for deciding on treatments for a patient, evaluating current interventions and for surveillance for disease presence (see below). However, this is not possible if the tool does not work properly! Often, developed tools are not practical yet in the field. To find out how the test can be best put into use, evaluation is necessary. Here, we distinguish ‘outbreak-use’ diagnostics.
Outbreak-use Diagnostics
When an emergency outbreak occurs, it is of the highest need that a diagnostic becomes available of reasonable assurance of safety and effectiveness in the shortest amount of time. Therefore, a preliminary ‘outbreak-use’ diagnostic is developed and applied in the field as soon as possible [1]. This outbreak-use diagnostic or OUD is used determine who is affected, how the disease is transmitted and how the disease is spreading. This data is of utmost importance for development of containment strategies, and in turn for limiting casualties.
However, such a test has not gone through extensive performance trials yet. These trials would have taken a lot of time during which the epidemic could have caused many casualties.
Instead of figuring out all best practices of the OUD during long clinical trials, the performance and main best practices are discovered in the field, so in uncontrolled environments. We learned that this is the scenario where Mantis can be applied best.
Marianne van der Sande: A modular tool sees use when there is an outbreak of a pathogen where no convenient diagnostic already exists. The device should have advantages that make it attractive to use, for example cost-wise or through ease of use.
Through evaluation of these practices and the data on the health threat, diagnosis can be improved and the disease can be tackled more efficiently. Mantis facilitates collection and sharing of this data, by e.g. clear labeling and data storage on a SD card. See more on the application page. Gathering this test performance data also facilitates approval of the diagnostic for later use by the WHO [1].
Performance assessment of Diagnostic
So how do you know if your OUD functions perfectly? How can you ensure maximum specificity and robustness of your device? For this, the World Health Organization (WHO) has developed special rules.
The basic requirements for a diagnostic test are collected in the ASSURED program (Affordable, Sensitive, Specific, User-friendly, Rapid and robust, Equipment-free and Deliverable to end-users), developed by the WHO in 2003 [2]. link to front page/background? If these criteria are met, the diagnostic can be applied for use in the local area. Performance tests are still desired to improve its weak(er) points through a continuous feedback loop with the field team, elongating the lifespan of the system in the process. A diagnostic test that would fit these demands would be of great value for neglected diseases like African Sleeping Sickness [3].
To facilitate evaluation on-site in non-developed environments the TDR, the Special Program for Research and Training in Tropical Diseases, set up a guide including the general principles and best practices of evaluation [4].
References
- WHO, WHO to develop Essential Diagnostics List, World Health Organization, 15 June 2017, www.who.int/medicines/news/2017/WHO_develop_essential_diagnostics_list/en/.
Step 12. No more outbreak? - Monitoring
Once an outbreak is over, it would seem that everybody is saved and the danger of infection is gone. However, the infective agent can always adapt and spread to a population again. To make sure these resurgences are noticed early and handled quickly, again detection kits are necessary. These are mainly used for ‘case finding’ in the population.
For example, in the case of HAT small teams of doctors are travelling to random villages in the risk area. Here, the population is tested for trypanosomiasis. If the levels of infected people increase, this might indicate the rise of a new epidemic. Once this is measured, standard protocols for public education and prevention mechanisms are put into practice.
Dr. Marianne van der Sande
After the big peak of the epidemiology, diagnostics are still applicable (depends on the pathogen) but only risk groups relevant for the disease will be diagnosed. This requires characterization of the disease.
From dr. Marianne van der Sande we learned that it is hard to predict where an epidemic might reoccur. This is due to the fact that pathogens have a diverse effect on each segregation of the human population, due to the different genetic makeup of each different person and due to corresponding resistances.
Also, we learned from dr. Erwan Piriou that developing diagnostics for the new targets is often difficult, but our system has the advantage of being modular and easy to scale-up.
The case of Ebola (accordion) “One of the major success stories of outbreak prevention by diagnostics is Ebola, which was in the unique position of getting a lot of funding and research interest. Its dangerous characteristics caused fear worldwide, leading to large amounts of media coverage, resulting in previously mentioned funding and research interest. However, apart from Ebola, diseases with the potential of becoming an epidemic are often hard to control with diagnostics. For one, it impossible to screen for an unknown disease, which is often what a new outbreak is.”
When recurrence prevention of an outbreak is the goal of the diagnostic, the difficulty lies in funding. Preventing recurrence comes down to screening in the field with diagnostics. Small ‘mobile teams’ are then send into the field to perform active case testing. Every year after the epidemic, the mobile teams are send out to test random villages. If no case is found in 5 years after the last case, the mobile teams become active only once every three years.
To overcome the funding problem, the WHO is setting up a list of Essential Diagnostics which should center the funding better [1].
References
- WHO, WHO to develop Essential Diagnostics List, World Health Organization, 15 June 2017, www.who.int/medicines/news/2017/WHO_develop_essential_diagnostics_list/en/.
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