The Rapidemic kits are unlike other tests in that they present certain unique features. We have reflected on the insights that we have gained from experts during our Human Practices to envision the implementation of Rapidemic worldwide. We have imagined an ambitious and innovative implementation plan that would emphasize accessibility and equality. In this section we drew out the journey from development to manufacturing to distribution and validation, to finally reach the patients during an outbreak.
Rapidemic could be part of an epidemic preparedness strategy because of its modularity. Modification of the generic kit to a specific pathogen is accomplished easily and quickly. Thus, rapid response to an outbreak is possible. Rapidemic adapts to a new pathogen much faster than antigen-based tests 1. The validation of new antigen-antibody interactions is less straightforward than the validation of nucleic acid-interactions for a new set of primers. When a sudden outbreak of an unknown pathogen arises, the genome of the pathogen will be sequenced and based on the sequence a primer set will be designed. Subsequently, the primers are put into the generic kits, making the kits pathogen-specific and ready for validation and distribution.
1. Distribution of generic Rapidemic kits
Rapidemic consists of two components, a generic kit, and a primer set. The first can be mass-produced in advance and distributed. This allows us to have generic kits in place before an outbreak occurs. Since we plan to lyophilize the vulnerable enzyme content and make the body of our kit airtight, it should be more resistant to outside conditions, such as temperature and humidity. This in turn could improve its shelf life, allow for long-term storage, and help to retain quality performance until an outbreak occurs.
Distribution of generic Rapidemic kits in low resource areas
It was recommended by stakeholder Guus Eskens to carry out production in high-resource areas. While it is possible to produce diagnostic tests locally in low-resources areas, the majority of such products are imported. Especially for RDTs, the technical knowledge required is often insufficient in low-resource areas and manufacturing is therefore diverted to countries such as China, Malaysia, or India. After the mass-production, the generic kits can be distributed. However, global distribution and transportation in low-resource areas demand careful consideration in regard to the following aspects.
Several currently existing RDTs, such as one for Ebola, require cold chain transport. As physical transport distance increases, temperature regulation becomes more challenging and costly. Rapidemic intends to circumvent this issue through the aforementioned lyophilization, which increases its resistance against fluctuating and/or extreme transport conditions, such as the severe heat experienced in countries close to the equator.
2. Outbreak of a pathogen
Scientists investigated different infectious diseases that may pose a potential pandemic threat 2. They made a list of virus groups that possess characteristics that are known to enhance the potential of pathogens to cause a pandemic. The list includes orthomyxovirus (influenza), respirovirus, henipavirus, rubulavirus, coronavirus, enterovirus, and rhinovirus. From the list, only influenza and enterovirus have systematic surveillance taking place. No vaccines nor effective antivirals exist for the other viruses on the list, making the human population vulnerable to future pandemics.
These viruses were included in this list because they hold characteristics that are prone to cause a pandemic. A pandemic is the result of the global spread of a microorganism between humans. There are different ways of transmission, whereof the respiratory route poses the greatest risk for pandemics. This is due to the difficulty of stopping the transmission using the standard public health measures. Another aspect which makes respiratory viruses form a greater risk is that many respiratory viruses possess RNA instead of DNA genomes. The RNA genome is prone to mutate, which increases the probability of outbreaks of novel pathogens. 2 This also complicates the (anticipative) development of vaccines and diagnostics. As explained in the sections below, Rapidemic can be easily modified to the mutated pathogen.
As we experienced towards the end of 2019, it can be incredibly frightening to experience the outbreak of an unknown pathogen, when its mode of transmission, the transmission rate nor the severity of the ensuing disease are clear. The first patients infected with the pathogen are brought to the hospital where saliva or blood samples are taken. Once the hospital staff identifies that they are dealing with an unknown pathogen, the samples are sent for further analysis to a (local) laboratory.
When such a new pathogen first emerges, researchers use samples from the first infected patients to isolate the causative agent. Afterward, it is sequenced to decode its genome which can be compared to existing infectious agents. The same was done during the outbreaks of SARS-CoV-2 or H1N1 3,4. As soon as they are identified, the gene sequences are uploaded to online, open-source databases, such as Genbank of the National Center for Biotechnology Information (NCBI), to make them accessible to researchers across the globe 5.
4. Primer design and completion of the Rapidemic kits
Once the genome has been unravelled, researchers attempt to identify a sequence in the genome of the pathogen that is unique, and would enable them to single out the patient samples that are infected by the same pathogen. Thereafter, they synthesize bits of single-stranded DNA that are complementary to the unique sequence of the pathogen, called primers. In PCR, the most commonly used diagnostic test, the primers bind the DNA or RNA of the pathogen and amplify the selected part. Eventually, the presence of many copies of the sequence indicates that the pathogen with the corresponding sequence was present in the sample.
This technique is so crucial for diagnostics in laboratories and hospitals meanwhile the pressure during an outbreak is immense. Therefore, the sequencing and development of the PCR primers sometimes require just a few days. International collaboration is central as the open-access publications allow laboratories from around the world to synthesize these primers and, in turn, identify infected patients using PCR. A challenge of this technique, however, is to identify a suitable reference sample. This can be complicated at the beginning of an outbreak, as the symptoms may not yet be clear-cut and conclusively identifying infected patients based on their symptoms or microscopy is intricate.
Similar to PCR, Rapidemic solely requires the addition of primers to make them pathogen-specific, ready for use and functional, which renders this technique versatile and suitable for a rapid epidemic response. The primers can be produced by local partners in molecular diagnostics and genomics, which would decrease the time required to generate complete test kits and therefore introduce less delay in the response. Additionally, this would reduce and redistribute the strain on large diagnostic companies as well as the probability of running out of reagents. Our team had imagined that the primers could be introduced in the generic kit together with the patient sample, to avoid extensive manipulations and risk of contaminations.
This endeavor requires interplay between many players to ensure rapid access to quality testing. To safeguard the robustness and the consistent quality of the completed kits, manuals will be shared comprising the requirements for the design of the primers, which could be done in-house or outsourced. Additionally, the customers will receive instructions detailing the amount of primers and buffers to add to the kit as well as the sampling procedure and introduction into the kit.
5. Validation of the kits
After the kit is completed (generic kit + primers), it should be validated and approved by notified bodies, as is required for all medical applications. This will inevitably result in a slight delay in the response time to the outbreak. However, it is crucial to ensure the quality of the tests, for instance, by determining the specificity and selectivity of the tests containing the primers for the unknown pathogen. It is thus important to obtain external, independent testing and approval for the Rapidemic test. Furthermore, the current pandemic has taught us that many companies, not always as transparently, started commercializing tests of unknown quality 6,7. Therefore, external approval is necessary to build a good reputation when it comes to testing quality and to gain the trust of large organizations, like the World Health Organization. Validation and recommendation by these players increase the trust of individuals who might purchase tests for themselves, but more importantly of governments and NGOs who rely on the guidelines put forth by these international organizations.
Based on the input our team received from several business-oriented stakeholders, it became clear that Rapidemic should start building its reputation by testing a small range of pathogens. This would demonstrate the capacity of the kit to accommodate various primer combinations while maintaining high-quality results. An example of an interesting pathogen class is the class of respiratory-borne RNA viruses, which amongst others includes coronaviruses and influenza viruses.
Every human being has the right to health care and testing as stated in the Universal Declaration of Human Rights8. In line with human rights and the Sustainable Development Goals, we aim to avoid a situation of urgency where the capital determines the allocation and accessibility of tests. We want to prevent a monopoly position for high-income countries which would leave low-income countries empty-handed. To ensure equality between high- and low-income countries, we have come up with the idea of implementing a hybrid economic model. This business plan originated during our extensive human practices and was highly praised by the stakeholders and experts we have contacted.
The proposed model entails that the generic kits are paid for and distributed in advance, as part of epidemic preparedness. The income generated by the sale of kits in high-income countries would help fund the purchase of the kits by lower-income countries or NGOs. Therefore, the price of our kit would be tailored to a country's capacity to afford these. The hybrid income model is intended as an effort for more equality and accessibility to healthcare for all countries.
7. End users
The aim of our test kit is not to directly compete with centralized (PCR) testing, but to complement it.9 Our kit is aimed at more niche settings, where centralized testing either falls short or is not in place. We intend to bring our kit outside a hospital lab to provide rapid point-of-care testing. This allows our kit to be used in for instance airports, schools, elderly homes, or crucial businesses. In low-resource countries, where PCR diagnostics are often not available, our kit could assist or set in place centralized testing.
In September 2020, news came out in our native country, The Netherlands, that school boards were paying over 100 euros per test in order to test their teachers for COVID-19 in commercial facilities.10 They did this because the centralized testing procedure in our country required the teachers to stay home for over four days to wait for their test result. This cost the schools large sums of money and this, together with the teacher shortage our country was already facing, led school boards to the decision that their best solution is to invest money in rapid commercial testing. This choice is very unfortunate considering that teachers have been underpaid in our country for decades and this will likely not change because of the economic consequences of the current pandemic.11 Rapidemic could pose a far cheaper alternative to commercial testing with equally high accuracy. By implementing our test kit in case of an outbreak, test results can be obtained in approximately 1 hour, allowing for teachers to jump right back into teaching if the result comes back negative.
Furthermore, our kit could be used in elderly homes. During this pandemic, it has become very difficult for people to visit their loved ones in elderly homes because of fear of contamination. This has resulted in increased loneliness amongst the elderly.12, 13 Rapidemic could enable point-of-care testing, allowing elderly homes to screen visitors at the door. That way people will not have to make a choice between spending their final days alone or dying as a result of infection.
Another crucial setting we identified concerns airports. To prevent the international spread of a virus it is important to test incoming travelers, especially those coming from risk areas. Rapidemic could be used in airports to quickly test travelers without the need of an external laboratory to perform the test, allowing them to get their result before entering the plane.
In low-resource countries, the testing situation is often even worse. There generally is a lack of PCR equipment which makes it challenging to have centralized testing in place. Moreover, a point-of-care test is more beneficial than lab-bound testing in remote or isolated areas because it helps overcome logistical distribution issues. Our point-of-care kit will hopefully provide more perspective in a future outbreak by establishing more local testing to track down the spread of the virus.
- Peeling, R. W., Murtagh, M. & Olliaro, P. L. Epidemic preparedness: why is there a need to accelerate the development of diagnostics? The Lancet Infectious Diseases 19, e172–e178 (2019)
- Nuzzo, J., Mullen, L., Snyder, M., Cicero, A. & Inglesby, T. Preparedness for a High-Impact Respiratory Pathogen Pandemic. Apps.who.int (2019). at https://apps.who.int/gpmb/assets/thematic_papers/tr-6.pdf
- Ciotti, M., Angeletti, S., Minieri, M., Giovannetti, M., Benvenuto, D., Pascarella, S., ... & Ciccozzi, M. (2019). COVID-19 outbreak: an overview. Chemotherapy, 64(5-6), 215-223.
- Pandemic (H1N1) 2009, Influenza Virus Resource. Ncbi.nlm.nih.gov (2020). at https://www.ncbi.nlm.nih.gov/genomes/FLU/SwineFlu2009.html
- NCBI. Genome. Available at: https://www.ncbi.nlm.nih.gov/genome (Accessed: 21st October 2020)
- Kopel, J., Goyal, H. & Perisetti, A. Antibody tests for COVID-19. Baylor University Medical Center Proceedings 1-10 (2020). doi:10.1080/08998280.2020.1829261
- Commission, U. S. S. and exchange. Look Out for Coronavirus-Related Investment Scams - Investor Aler. 4-2-2020 Available at: https://www.sec.gov/oiea/investor-alerts-and-bulletins/ia_coronavirus(Accessed: 21st October 2020)
- United Nations. [Universal declaration of human rights]. Z. Krankenpfl. 61, 499–502 (1968).
- Roche. Centralized vs. decentralized testing models and the importance of both for COVID-19 testing [internet]. 2020 [cited 26 October 2020]. Available from: https://diagnostics.roche.com/us/en/roche-blog/centralized-vs-decentralized-testing-models-and-the-importance-o.html
- NOS. Wachttijd coronatest te lang, scholen lopen warm voor commerciële aanbieders [internet]. 2020 [cited 26 October 2020]. Available from: https://nos.nl/artikel/2346814-wachttijd-coronatest-te-lang-scholen-lopen-warm-voor-commerciele-aanbieders.html
- Dutchnews. Over 4,000 schools closed as teachers strike over pay and working conditions [internet]. 2020 [cited 26 October 2020]. Available from: https://www.dutchnews.nl/news/2019/11/over-4000-schools-closed-as-teachers-strike-over-pay-and-working-conditions/
- The Guardian. They could die of loneliness: how Covid policies impact care homes [internet]. 2020 [cited 26 October 2020]. Available from: https://www.theguardian.com/world/2020/sep/14/they-could-die-of-loneliness-how-covid-policies-impact-care-homes
- Thenationalnews. Coronavirus: elderly dying alone in western care homes deserve a lot more dignity [internet]. 2020 [cited 26 October 2020]. Available from: https://www.thenationalnews.com/opinion/comment/coronavirus-elderly-dying-alone-in-western-care-homes-deserve-a-lot-more-dignity-1.1015809