The Covid-19 coronavirus is speeding past all the stop signs that countries have put in its way. How can we put the brakes on the pandemic?

One solution is faster, more accurate testing to ensure carriers are identified and go into isolation before infecting others.

It can take one to five days to get results from the standard reverse-transcription polymerase chain reaction (RT-PCR) test to identify the virus’ RNA genetic material on nasal and throat swabs.

Wait times are longer because of high demand and because samples must be sent to a lab from the point of care and are manually processed.

Furthermore, a negative result may mean only that the viral load wasn’t yet detectable on the day you were sampled, says Dr. Moran Szwarcwort-Cohen, director of the virology lab of Rambam Health Care Campus in Haifa, one of about 40 coronavirus testing labs in Israel. “The next day, you might test positive.”

Szwarcwort-Cohen tells ISRAEL21c that the most critical need is fast testing at the point of care. Probably more than one type will be deployed.

“They will come into use soon, but I cannot say how long it will take to get validation and approval for each new technique and technology,” she says. “We need to know the limitations of each technique, how to use it and how to interpret the results.”

But Israel is a small country, and the validation process requires many patient samples. That’s why the Ministry of Defense Directorate of Defense Research and Development is sending a delegation to India with four Israeli Covid testing prototypes.

The Israelis will collect tens of thousands of samples in 10 days and analyze them using a “voice print” analysis technology from Vocalis, a breathalyzer test from the Tera Group, an isothermal test being developed by Rapid Diagnostic Systems, and a polyamino acid test from Kidod.

Below are details on a range of proposed Israeli testing solutions.

Rapid no-lab test kit

Rambam Health Care’s research collaboration with the nearby Technion-Israel Institute of Technology is yielding a variety of Covid testing solutions.

One is a rapid test using saliva samples mixed with reactive material and then placed in a thermal cup with hot water. Color-coded results appear in about 40 minutes, yellow for positive or pink for negative.

This method could become the basis of a mass testing kit for workplaces, points of care and households, says Technion Prof. Naama Geva-Zatorsky.

Her lab developed the technique with the involvement of Szwarcwort-Cohen; Dr. Mical Paul, director of the Infectious Diseases Institute at Rambam; and Prof. Michal Chowers, chief the infectious diseases unit at Meir Medical Center. It is being developed by Rapid Diagnostic Systems (see above).

The test’s reliability was measured using 200 biological samples from confirmed coronavirus patients and patients suspected of infection with the virus, supplied by Rambam’s coronavirus biobank.

Geva-Zatorsky said the test identifies 99% of cases when there are medium or high concentrations of the virus. Her lab is now working to improve sensitivity to the presence of the virus in low concentrations.

“We see this test as suitable for use at entrances to hospitals, workplaces, nursing homes, airports, and in drive-through facilities,” she said.

“The most significant innovation,” said Chowers, “is that the test can be carried out on site, within an hour, eliminating the need to send the saliva to a special lab.”

The pooling method

Szwarcwort-Cohen and Technion Prof. Roy Kishony innovated a pooling method for accelerated Covid-19 testing that’s getting worldwide attention.

Pooling is not a point-of-care solution. Its goal is speed: It enables RT-PCR testing to be performed on a combined sample from 32 or 64 patients, significantly accelerating the testing rate.

If a pooled sample tests positive, individual tests are done to find the sample (or samples) causing that result.

“It’s best for monitoring general populations where the infection rate is 5% or below — towns or cities, groups like army units, or essential factory workers working in capsules,” Kishony tells ISRAEL21c.

“If you pool samples from those groups, then in one test you get an indication whether the group as a whole can function. If one is a carrier, they may all be sent home.”

Kishony says countries including India, Singapore and Hungary are reorganizing testing labs to accommodate pooled testing, and Western countries are following their lead.

“Although there are some logistical challenges in implementing the method, we expect that it will greatly increase the volume of samples tested per day so that we can identify the asymptomatic carriers. This approach should reduce the chance of infection and flatten the infection curve.”

A simple pooling technique for testing eight samples at once, developed in the lab of Prof. Yuval Dor at Hebrew University, is already in use throughout Israel. Prof. Tomer Hertz’s computational immunology lab at Ben-Gurion University also is working on a pooling strategy.

BATM fast-result test kit

In March, BATM of Hod Hasharon introduced a diagnostics kit to detect Covid-19 from saliva samples in about half an hour, using the current RT-PCR method.

“We are selling it in large quantities in the Far East and Latin America, but not yet in Israel or the United States,” says Dr. Zvi Marom, CEO. “We are waiting for FDA clearance.”

Meanwhile, on July 15 BATM announced three new test kits to diagnose Covid-19 and other respiratory illnesses. Production is to begin at its Adaltis facility in Italy by the fourth quarter of 2020.

The first is a new molecular diagnostics test that can identify and differentiate among prominent respiratory viruses, including all strains of Covid-19, flu and the common cold, even in asymptomatic people. It can also detect the bacteria that cause pulmonary illnesses believed to be a secondary infection of Covid-19. This 30-minute test was developed in collaboration with Tor Vergata University in Italy.

BATM is developing an RT-PCR rapid diagnostic kit for coronavirus. Photo: courtesy

The second is the world’s first Covid-19 antigen test to include five genes – most test for two or three — including the “spike” gene that the virus uses to invade human cells. The spike gene is present in a person’s blood even when the viral load of Covid-19 is too low to be detected. This kit, expected to receive CE certification shortly, can run on any standard PCR instrument.

The third new kit from BATM is a Covid-19 serologic test to measure the quantity of antibodies in the blood rather than just the presence or absence of antibodies in recovered patients.

Marom says this test was developed in response to new medical research suggesting that antibodies in the blood of recovered patients are few and fade fast. “As such, it is an important tool for estimating herd immunity and the efficiency of future vaccines.”

“Around September, we will introduce flu and Covid rapid sputum tests, which test for the virus rather than for antibodies,” he tells ISRAEL21c.

Rapid breath test

Scentech Medical is doing a trial of its RBT (rapid breath test) at Meir Medical Center in Kfar Saba ahead of finalizing the prototype design.

“All other companies are developing a method to look into the virus or its effects, but we are actually getting a fingerprint of the disease,” Executive Board Member Rom Eliaz tells ISRAEL21c.

“Our lungs send out 8,000 to 14,000 volatile organic chemicals. They differ from one person to another and can reveal the presence or status of a disease,” he explains.

“We are hoping to identify not just whether you have Covid but what stage you are in, so we can know how long you should be in isolation.”

Scentech’s original focus was cancer detection. “We have great results in breast, colon and colorectal cancer,” says Eliaz. “Then we got a request from the Health Ministry to use our technology for Covid-19.”

He envisions the breath-test devices being placed at border crossings, airports and large venues like sports stadiums. Eliaz said each noninvasive check would take about 10 seconds.

But first, Scentech must finish the hospital test to assure at least 85% accuracy and then do a larger study to validate results.

“We already have signed contracts with a few companies for distribution in Singapore, South Africa, Turkey and other countries. We need regulatory approvals but with Covid19 devices that is happening very fast,” says Eliaz.

Applying AI to testing

Diagnostics.ai introduced pcr.ai software that uses artificial intelligence (AI) to analyze PCR tests. It eliminates human error, assures standardization and enables doubling the number of samples tested per day without additional staff.

“We integrate with existing PCR tests and remove the need for people to analyze the data. This is really critical because usually data is reviewed by two experienced lab scientists, but during the Covid pandemic a lot of labs are being staffed by less experienced volunteers and this can lead to errors,” says cofounder and CEO Aron Cohen.

After testing in Europe, the pcr.ai software robot is now analyzing hundreds of Covid samples daily at King’s College Hospital NHS London, the city in which Diagnostics.ai is headquartered. The R&D team is based in Israel.

“We have a commercial contract with a CLIA lab in the US for their Covid testing and we’ve had requests from many labs and countrywide distributors everywhere,” says Cohen. That includes Israel, where a distribution deal was recently signed.

Spectrometer-on-Chip

Newsight Imaging of Ness Ziona is beginning a pilot of its Spectrometer-on-Chip rapid Covid-19 test at Sheba Medical Center.

Newsight claims the computer mouse-sized device can detect viruses in a blood serum or saliva sample in less than a second.

Spectral technology for virus detection is not new, but it’s prohibitively expensive. Newsight’s innovation is putting this technology on a single cost-effective chip, using an AI algorithm to detect specific types of viral infections.

Infectious and tropical disease experts at Sheba did initial feasibility studies of the device, proving its ability to distinguish between alpha-coronaviruses (Alpha-CoV) and beta-coronaviruses (Beta-CoV) accurately. They also did feasibility studies on blood serum samples of people infected with the Dengue virus.

Newsight and Sheba’s ARC Innovation Center intend to establish a joint company to commercialize the device, which would need regulatory approval.

“Newsight is yet another outstanding example of how ARC@Sheba Medical Center and the Israeli startup ecosystem are working in tandem to reinvent existing technology to battle the scourge of Covid-19,” said Dr. Eyal Zimlichman, Chief Medical and Innovation Center at Sheba Medical Center.

Newsight Imaging has already sold a license to develop virus and bacteria detection devices to the artificial intelligence company AIinnoBio from Hong Kong. Its spectral devices are also being developed for water quality monitoring through a collaboration with Mekorot, Israel’s national water company.

Terahertz-frequency speedy tests

Two solutions in development rely on terahertz (THz or T-ray) ultrahigh frequency radiation waves for early detection of the virus – without the reagents necessary for RT-PCR tests.

The Israel Ministry of Defense’s Directorate of Defense Research & Development is working with the Tera Group on a T-ray device intended for airports that could reveal within 60 seconds if a person is positive for Covid-19.

Ben-Gurion University of the Negev Prof. Gabby Sarusi, an electro-optical engineering expert. Photo by Dani Machlis/BGU

In addition, electro-optics researcher Prof. Gabby Sarusi of Ben-Gurion University of the Negev introduced an inexpensive point-of-care test that identifies Covid-19 within 60 seconds using THz spectroscopy.

“This virus resonates in the THz frequency, and spectroscopy in these frequencies reveals it promptly,” said Sarusi.

Particles from a simple breath test or throat and nose swabs are placed on a chip with a dense array of metamaterial sensors that analyze the sample quickly.

The results are saved on a database that can be shared to help track the course of the virus, as well as triage and treat patients.

The fast Covid-19 electro-optical diagnostic test. Photo by Prof. Gabby Sarusi

Because this test is electro-optical, it is not sensitive to environmental factors that can affect results of current biochemical testing methods.

Clinical trials done in conjunction with the Defense Ministry on more than 120 Israelis had a better than 90% success rate. The device originally was hoped to receive regulatory approval rapidly and go on the market in the fall.

However, investment and development are likely to be significantly slowed by a legal battle regarding the IP of the invention now being waged between BGU’s tech-transfer company and The Ram Group conglomerate.

A team from the Israel Ministry of Foreign Affairs was recently on the Marcus Family Campus to film Prof. Gabby Sarusi in his lab demonstrating the one-minute breath test. The Israeli Breathalyzer is an ultra-fast coronavirus test which would be positioned in points of entrance & help keep people safe.

פורסם על ידי ‏‎Ben-Gurion University of the Negev‎‏ ב- יום חמישי, 28 במאי 2020

Optics and magnetic particles

A technology developed in the engineering lab of Amos Danielli at Bar-Ilan University uses a combination of optics and magnetic particles to test 100 saliva samples in approximately 15 minutes.

The technology was already proven to reduce the diagnostic time of Zika virus and is currently being used in the Ministry of Health’s central virology laboratory at Sheba Medical Center.

The technology attaches the virus’ RNA to a fluorescent molecule that emits light when illuminated by a laser beam. At very low concentrations of RNA, the signal emitted is so low that existing devices cannot detect it.

“If we think of the saliva of a corona patient filling an entire room, then this laser beam can be compared to the size of a fist and at low concentrations of virus RNA, there might be only two or three fluorescent molecules within that fist,” explained Danielli.

Adding magnetic particles to the solution enables them to adhere to the fluorescent molecules. This enables a greater concentration of fluorescent molecules and a much more accurate measurement.

“We alternately operate the electromagnets, once on the left and once on the right, moving the molecules from side to side, in and out of the laser beam. As they pass through the laser beam, they become illuminated. When they exit the light beam, they are no longer illuminated,” Danielli explained.

“This flickering allows us, without any additional procedures, to accurately determine whether a person has been exposed to coronavirus.”

MagBiosense, a medical device company founded by Danielli to make lab-quality testing available at point of care, will further develop this innovation.

Magnetic beads

Magnets are also featured in a faster, cheaper Covid-19 test developed by researchers and students working with Prof. Nir Friedman at Hebrew University’s Institute of Life Sciences and School of Engineering and Computer Science and Naomi Habib of the university’s Safra Center for Brain Science.

“The RNA extraction protocol we developed is four to 10 times faster than the current protocol. It’s based on magnetic beads and works both robotically and manually,” said Habib. “The robotic protocol has already been tested at Hadassah and is now fully operational.”

The team performed hundreds of tests on swab samples at Hadassah Medical Center and the results they received were identical to those found by the kits currently being used.

“The Ministry of Health is testing our homemade kit as one of the options to replace the existing commercial kits throughout Israel,” Habib tells ISRAEL21c. An existing company is poised to take on the manufacturing and support.

Now, the Hebrew University scientists are developing a “multiplexing” method based on next-generation sequencing, which would enable testing tens of thousands of samples simultaneously.

Unlike standard pooling, with this method each sample is molecularly barcoded so that if a batch tests positive the individual positive sample(s) can be identified without further testing.

“We showed its potential on a smaller subset. Now we have a beta version we are starting to test at Hadassah on clinical samples,” says Habib.

“If it works, then other than potentially performing tens of thousands of tests at once for a cheaper price, it could add information we don’t get from the current test, like the strain of the virus. We can test and monitor multiple viruses at once.”

Mobile lab

Rehovot-based AID Genomics offers the AID Genomics Portable Mobile PCR Lab — a suitcase-sized mobile testing solution said to yield results in about 45 minutes.

The AID Covid-19 RT-PCR test setup could be deployed at point of care, including large venues, and administered by a medic or emergency medical technician. The analysis is automatic.

Chief Scientific Officer Izhak Haviv was quoted as saying the AID Genomics kit requires less RNA than others to determine whether a person has coronavirus. He claims that it is 50 times more sensitive than current tests.

The company has partnered with China’s BGI Group in Israel to develop the kits and to set up analysis centers and technical support at six Health Ministry labs. Haviv said he hopes that the kit will be approved for commercialization by the fall.