The Israeli Health Ministry has approved the first methods for making the process of testing for coronavirus more efficient through the use of pooling.
The first method, which was developed by researchers from Ben-Gurion University of the Negev, the National Institute for Biotechnology in the Negev and Tel Aviv's Open University, enables clinical labs to simultaneously analyze nose and throat swabs taken from eight people, helping the save reagents necessary for the process, which are in short supply all over the world. The second method, developed by high-tech company LessTests, offers a dynamic algorithm that makes the tests between two times and 15 times as efficient, correspondingly to the estimated prevalence of the virus in a given population.
The first new method, known as combinatorial pooling, was described in an article published on Friday in the journal Science Advances. It was developed by scientists from Ben-Gurion University of the Negev, the National Institute for Biotechnology in the Negev and Tel Aviv’s Open University.
Pooled testing has received unprecedented attention since the coronavirus pandemic began and health authorities all over the world realized they needed to make the testing process for the virus much more efficient. The U.S. Food and Drug Administration has since approved the use of two pool testing methods, but the new one approved by the Health Ministry in Israel is much more advanced and efficient – and outperforms other methods used in labs around the world over the past few months.
The development of the new pooling method was led by Profs. Angel Porgador and Tomer Hertz from Ben-Gurion University and the National Biotechnology Institute, along with Prof. Yonat Shemer-Avni, the director of the virology lab at Soroka Medical Center in Be’er Sheva, and Dr. Noam Shental of the Open University.
Prior to the Health Ministry’s approval, the Open University and Ben-Gurion University formed a joint company to develop and market the new testing method. Poold Diagnostics opened its research and development lab at the Biotechnology Institute.
Now the scientists are working in the R&D lab to achieve another ambitious goal set for them by Ben-Gurion University President Prof. Daniel Chamovitz: To build and validate a system for coronavirus testing using saliva, using their sophisticated pooling method. This would allow thousands of students to be tested every week once the academic school year opens in October after the Jewish holidays, thus permitting students to return to campus while still adhering to coronavirus health standards.
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Pool testing was first used during World War II to identify soldiers who had contracted syphilis. The basic idea behind pooling is to combine a number of samples into a single sample and test the pool. If the pooled sample tests negative, then all the individuals who were tested are not ill with the disease. Only if the pooled sample tests positive is it necessary to repeat the tests for each of the individual samples – to identify the specific person, or persons, who are ill. This makes testing faster and saves money and materials.
The new method is much more complex and sophisticated. It takes 384 samples and divides them into 48 pools, each of which has material from 48 original samples. The process of calculating and implementing this complicated distribution of the samples cannot be done manually by lab staff, so part of the new system includes adapting a lab robot to do the pooling.
After the robot completes the preparation of the pooled samples, the tray with the 48 pooled samples is run through the regular clinical lab PCR (Polymerase Chain Reaction) tests to detect the virus RNA. The results are processed automatically by software written by the developers of the method, which knows how to identify which of the original 384 people tested are positive or negative – and the results are then automatically sent to the medical files of the people tested on the labs’ computers.
Shental, from the Open University’s computer science department, developed the pooling method along with others in a theoretical paper published in 2010. At the time, it was intended for identifying rare genetic variants. In 2016, Shental and his colleagues published experimental validations of the method identifying rare genetic variants in sorghum plants.
Hertz said that in March, Shental called him and proposed implementing the pooling method for SARS-CoV-2 diagnostic testing. Two days later, Hertz began running the first experiment to calibrate the testing system in his lab at the Biotechnology Institute. A week later, they received leftover samples from the virology lab at Soroka, and began testing. After validating that their new method succeeded in identifying all positive samples, they conducted a clinical trial in cooperation with Dr. Lior Nesher, who heads the employee clinic at Soroka.
This clinical test started at the beginning of April and 1,115 hospital employees were tested as part of the study – and all were found to be negative. At the same time, the scientists got in touch with the Health Ministry and the coronavirus command and control center. Ronen Walfisch and Dr. Yuval Cohen of the Defense Ministry’s weapons and technological infrastructure development administration (Mafat), who headed the group for improving the efficiency of Israel’s coronavirus testing system, prepared a pilot program to validate the pooling method together with the Health Ministry.
At the beginning of May, the proposal was presented to the ministry for approval – and the scientists were informed of the experiments they needed to successfully complete in order to prove their method was effective and accurate enough.
The second pooling method to be approved was developed by a team led by entrepreneurs Ruth Polachek and Tsvika Vagman. They say that they started working on their development in February-March. At a certain stage, they were in contact with the group at Ben-Gurion. Then they were working also with the researchers at the Technion – Israel Institute of Technology, headed by Prof. Roy Kishony, who were researching the topic of pooling.
In the end, in coordination with the control center, they conducted validity tests and the approval of their method in the Health Ministry's central lab. For this purpose, they developed software and algorithms that interface to the various systems of the Health Maintenance Organizations, and allow directors of everys lab to choose the pooling method most suitable to their conditions.
The software by LessTests, make a weighted calculation of the various parameters and suggests the optimal pooling parameters. When the prevalence of the virus in a given population being tested is 1 percent or less, their algorithms can suggest an increased efficiency of up to 20 times relative to normal tests.
They add that the uniqueness of their method is that efficiency remains even when the prevalence in a population rises above 8 percent, without the need to reallocate samples like in other methods.
Now that the method has been approved by the Health Ministry and published in a scientific journal, the scientists who developed the two different methods want to promote its adoption in clinical virology labs all over Israel. “Many labs have already been in contact with us, and waited for us to receive approval,” said Hertz. “We are now working on building a system to identify [coronavirus] carriers using saliva samples instead of swabs,” said Shental.
Various protocols for testing saliva samples have been published around the world in the last few months. This is supposed to remove the major bottleneck of collecting the swab samples, which requires professional staff members. In addition, saliva sampling reduces the possibility of infecting medical staff.
Hertz said that Chamovitz set a goal for them: “To set up by the beginning of the academic school year a testing system for all the students who come to campus every week – between 2,000 to 3,200 people.” The goal is to keep track of the percentage of infected people on campus. The possibility of allowing students to check their test results anonymously and then be able to request a clinical test if their result came out positive is also being considered.
Because the university is unable to collect thousands of swab samples every week, the entire system will have to be based on saliva samples – which every person to be tested can collect on their own. “This is a very ambitious goal,” Hertz admitted.
They also started working on implementing the testing method in other countries, with an emphasis on a pilot trial in the U.S. that would enable them to receive FDA approval. But the motive for the project was always to allow the expansion of the testing process in Israel, said the developers.
Shental and Hertz said that the person who made the breakthrough possible was Walfisch, an aeronautical engineer by training, who led the entire project on the side of the government bodies. “Many in the scientific community questioned the chances of the Health Ministry approving the use of such an advanced method for medical tests in Israel,” said Hertz. Calling the approval “a national milestone,” and he added that the country has come to the realization that it needs to make use of the most advanced science to handle the coronavirus outbreak.