Tag Archive: COVID-19

  1. Blumenthal, Murphy praise SalivaDirect after visiting Yale School of Public Health

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    Connecticut Sens. Chris Murphy and Richard Blumenthal visited the Yale medical campus Tuesday morning and met with Yale scientists to discuss SalivaDirect, the new saliva-based testing protocol developed at Yale and validated with a study funded by the NBA. Among these Yale professionals were Dean of the Yale School of Medicine Nancy Brown and Dean of the Yale School of Public Health Sten Vermund.

    The initial research on using saliva samples was led by Anne Wyllie, associate research scientist in epidemiology, and Nathan Grubaugh, assistant professor of epidemiology. After obtaining promising results, they partnered with the NBA to validate the testing method on a larger cohort. The new saliva-based testing protocol received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA) on Aug. 15.

    Both U.S. senators gathered on the lawn outside of Edward S. Harkness Memorial Hall after their meeting to reflect on how they envision SalivaDirect helping the state fight COVID-19.

    “This test is potentially a world-shaking, really game-changing breakthrough because it can reduce the cost, raise reliability and make detection and screening much faster,” Blumenthal said. “It can produce a low cost, very sensitive and very reliable kind of test that offers, right now, massive potential results for the country.”

    Blumental and Murphy applauded Yale researchers for committing to keep SalivaDirect inexpensive. After the protocol received EAU from the FDA earlier this month, Wyllie told the News that they sought to provide each test for $10 or less. A preprint published in early August estimated that the cost of reagents for each test would fall between $1.29 and $4.37 per sample.

    Blumenthal said his goal is to help scale up SalivaDirect while keeping it inexpensive. (Photo: Charlotte Zimmer)

    “Right now we have a set of reagents and instruments that have been included in the EUA,” postdoctoral fellow Chantal Vogels, who helped lead the EUA submission for the FDA, told the News last week. “By performing bridging studies, we can include other reagents, instruments [and] automated systems. We just have to show that that works equally well as compared to the components that we’ve already included and have authorized.”

    According to Vogels, the team is also planning on conducting bridging studies — supplemental studies that collect new data to expand the scope of the initial authorization — and working to identify equipment that other laboratories would find convenient and cost-effective for administering SalivaDirect. By identifying which bridging studies to conduct, the research team can validate the protocol with new instruments before submitting data to the FDA and seeking official approval to authorize a wider range of instrumentation for the protocol.

    Running a test according to this protocol will be much cheaper than the currently available tests kits that can cost around $150, according to Wyllie. Murphy emphasized that making testing more affordable will be the key to ending this pandemic and the damage it has caused.

    “There’s no amount of economic stimulus that Congress can provide to fix what’s broken in our economy, unless we beat the virus,” Sen. Murphy said. “And the only way you can beat this virus is to be doing ten to a hundred times more testing than we are today.”

    Murphy expressed frustration with the country’s inability to conduct population testing, but said he is “really grateful” to Yale researchers who are studying how to address testing shortages and lower the costs of testing. According to Murphy, tests are currently too expensive or hard to acquire, and businesses and schools in New Haven could have difficulties testing all essential workers and students. Large-scale population testing would help Connecticut reopen schools and the economy with more confidence, he said.

    The senators both discussed what their role would be in the next steps of developing SalivaDirect.

    “Our job now is to make it available to as many people as possible, as quickly as possible,” Sen. Blumenthal said. “And I think that my goal will be to enable that it be rolled out, scaled up [and] the intellectual property protected in a way that prevents a medical device company from profiting and exploiting this test, raising the price to put it out of reach from school systems or sports leagues…”

    “I’m going to be bragging to my colleagues down in Washington about the kind of test we developed here,” Blumenthal said. (Photo: Charlotte Zimmer)

    Researchers have already been addressing the challenge of disseminating the test. Unlike other testing kits that companies sell or distribute, SalivaDirect is the first testing protocol to receive an EUA from the FDA. The protocol is open source, and researchers at Yale have the right to authorize high-complexity U.S.-based labs seeking to begin testing with SalivaDirect, though any lab that receives approval must be certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA). 

    Although the team initially directed requests to an email address, researchers have now set up a Google Form to field authorization requests. Hundreds of emailed requests came in the 72 hours following the announcement of SalivaDirect’s EUA, Annie Watkins MPH ’21 told the News last week.

    The Yale Pathology Clinical Molecular Diagnostic Lab was the first to receive approval to use SalivaDirect, earning authorization as part of the terms of the FDA EUA. According to Pei Hui, the director of the lab, his group partnered with Grubaugh and Wyllie’s team early on to carry out the clinical validation of the testing protocol necessary for the EUA, which is something the epidemiology researchers could not do on their own.

    Hui said the lab first officially started using the protocol on Thursday, Aug. 20 and added that the approval of the Yale Pathology Clinical Molecular Diagnostic Lab for SalivaDirect is a step in the right direction when it comes to scaling up the test.

    “This is beauty. This is really significant progress in my view,” Hui said. “Being able to do saliva, the value is tremendous. I think it will be changing the COVID testing landscape in the US.”

    The lab had already been testing nasopharyngeal swabs throughout the pandemic. Hui said they expect to maintain this testing platform as they begin to incorporate saliva samples. 

    The lawn outside of Edward S. Harkness Memorial Hall, where Murphy and Blumenthal spoke on Tuesday. (Photo: Charlotte Zimmer)

    He explained that his lab is currently “limited in space and manpower,” but that they hope to expand the operation. His lab will potentially buy automatic machines and use lab space at West Campus, although this would likely take a few months to set up, Hui added.

    The researchers involved in SalivaDirect also contacted the Yale Testing and Tracing Committee to propose that saliva samples could potentially be used in testing the Yale community in the future, according to Hui. Both senators expressed excitement about the prospect of working with Yale to continue scaling SalivaDirect and its use.

    “It is a source of enormous pride,” Blumenthal said. “I’m going to be bragging to my colleagues down in Washington about the kind of test we developed here … There is no pharmaceutical company that should profit; no medical device company should make money from it. The benefits should go directly to the public.”

    William McCormack | william.mccormack@yale.edu  

    Charlotte Zimmer | charlotte.zimmer@yale.edu

  2. Automation, pooling could come next for SalivaDirect as research team juggles authorization requests, media attention

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    Chantal Vogels was not expecting the news on a Saturday morning.

    A postdoctoral fellow in the Grubaugh Lab at the Yale School of Public Health, Vogels helped lead the Emergency Use Authorization submission process for SalivaDirect — a new saliva-based testing protocol for COVID-19 — detailing validation data in the application and collaborating with the U.S. Food and Drug Administration as the process moved along.

    By last week, she could sense the EUA was nearing. She was trading daily emails with the FDA, while Nathan Grubaugh — assistant professor of epidemiology, principal investigator in the Grubaugh Lab and the lead researcher behind SalivaDirect, alongside associate research scientist in epidemiology Anne Wyllie — was spending lots of time on the phone with the regulatory agency.

    On Saturday morning, word suddenly came through: the FDA had issued an EUA for SalivaDirect, permitting other high-complexity laboratories to acquire the testing protocol for use and igniting a flood of popular attention.

    “I think none of us would have expected it to be this big,” Vogels said. “We knew that we were getting to like the final stages … I was expecting it to be Friday or Monday. And then when it came, the media attention has just been crazy. We’ve been so overwhelmed. It’s really amazing to see how well it’s [being] received.”

    Since the EUA has been issued, the team of scientists, accustomed to spending hours inside the lab and out of the limelight, has been ushered onto live news segments and quoted across the internet. Vogels, who is from the Netherlands and completed her bachelors, masters and PhD there, said family and friends in Europe were excited to see her appear live on CNN Monday. Grubaugh spoke with CBS This Morning and ESPN, while Wyllie did interviews with ABC News, MSNBC and more. A Twitter thread describing the test and its benefits from former Obama health care aide Andy Slavitt had garnered more than 22,000 retweets by Tuesday evening.

    Yet as the media attention from Saturday’s EUA has continued into this week, researchers have been even more focused on what might come next, continuing explorations into improvements for the test and outlining a process for disseminating their open-source protocol to interested labs. Researchers are exploring the automation of sample processing, pooling of saliva samples for improved efficiency and modifications to SalivaDirect that would speed up processing by replacing the polymerase chain reaction step.

    “Although SalivaDirect is a big step forward, it’s definitely not the end of it,” Vogels said. “It’s not the solution to everything … It’s a huge step forward, but it’s just one step of the many steps that are still ahead of us.”

    Aside from improvements to the test, one of the most pressing steps for the researchers is distributing authorizations to labs and other groups interested in using SalivaDirect. Annie Watkins MPH ’21, who is helping to process correspondence from interested parties, told the News that the Grubaugh Lab had already received “hundreds of” emails inquiring about authorization by Tuesday morning.

    As part of the terms of the FDA EUA, Yale’s Pathology Clinical Molecular Diagnostic Lab, led by Pei Hui, became the first laboratory authorized to administer and process SalivaDirect. All laboratories that subsequently receive authorization must be certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).

    Vogels and Watkins were not able to provide the names of any specific institutions or laboratories reaching out seeking authorization — and could not comment on whether Yale has inquired about using the test for its regular testing of students returning to New Haven this fall — but said the interest originated from a wide spectrum.

    “It’s pretty broad [in terms of] who’s interested in things,” Watkins said. “There’s definitely some universities, university health systems that are interested in return to campus, potentially athletics. And there are one-off labs, there’s a few private practice type things [and some] international labs.”

    The rollout has been complicated by the unique nature of SalivaDirect’s EUA. According to the Grubaugh Lab’s CovidTrackerCT website, SalivaDirect — which is not a testing kit for sale — is the first protocol to receive an EUA from the FDA. The protocol is currently posted as an open source, but “testing is limited to laboratories designated” by the Yale School of Public Health, per the terms of the FDA EUA.

    SalivaDirect is the first protocol to receive an EUA from the FDA. (Photo: Sonia Ruiz)

    Grubaugh wrote in a Twitter thread on Tuesday evening that due to the novel nature of the EUA, his team has to work with Yale and the FDA to come up with the legal conditions surrounding authorization as well as formalizing the regulation of the whole process. Once these regulations are in place, they will start by authorizing labs that will test schools, Grubaugh wrote.

    The lead researcher, whose lab previously studied mosquito-borne viruses before the emergence of COVID-19, also addressed some misconceptions surrounding the testing protocols. 

    “What isn’t SalivaDirect?” Grubaugh wrote. “It isn’t a point-of-care or an at-home rapid test. It uses PCR, and thus requires a high-complexity lab … We don’t have products to distribute. Rather, for authorized labs, we can provide a protocol for doing inexpensive saliva-based RT-qPCR testing.”

    He also noted that while SalivaDirect testing is not yet available to the public, the lab is working to create partnerships to allow for this in the future.

    According to researchers, the next innovations for SalivaDirect include automation, rapid detection and pooling.

    Automation will require the validation of robotic systems and will hopefully be applied to the sample processing and/or PCR steps. With regards to the second goal, Grubaugh wrote that they are also working on replacing the PCR step altogether, with either loop-mediated isothermal amplification or recombinase polymerase amplification. Pooling would allow researchers to combine saliva from many people and test it simultaneously, which could increase testing capacity and utilize reagent resources more efficiently. 

    Watkins said that running one plate with PCR ideally only takes three hours. But other variables, including transport time and high volume, can lengthen the process.

    “It really depends on the lab,” Vogels added. “There’s a step between collecting the sample, getting it in the lab, doing the test, sending out a result, so in an ideal world the protocol itself might be a couple hours, but it’s not a rapid test.”

    All laboratories that receive authorization must be certified under the Clinical Laboratory Improvement Amendments of 1988. (Photo: Lukas Flippo)

    The lab’s study with the NBA — which offered funding for the validation process — is ongoing as researchers continue to explore how SalivaDirect works for asymptomatic detection. They are monitoring samples from one team outside of the bubble, according to Watkins, after players have stopped testing positive in the Orlando bubble. Vogels said the NBA study is also being used to study pooling. 

    SalivaDirect’s current EUA permits the test for “individuals suspected of COVID-19 by their healthcare provider.” The team could submit another EUA for asymptomatic screening with data from the NBA study, Watkins said, but FDA rules around tests for asymptomatic surveillance continue to evolve.

    “As far as I know, I think there’s only one test or a few tests that have been authorized for testing asymptomatics,” Vogels said. “So I think this is really a dynamic process of figuring out what does it really mean, where can we apply this, and how does that really work, so we’re still working closely with the FDA to figure that out.”

    Finally, performing bridging studies could also allow researchers to show the FDA that using different reagents or instruments down the road might work just as well, helping make the testing protocol more flexible for a wider range of labs. 

    But first come the emails that continue to pour in. For the researchers, this journey has been all-consuming but rewarding nonetheless.

    “I’ve kind of forgotten that I’m a student,” Watkins said. “I’m supposed to be registering for classes this week, and I forgot the classes were a thing to be completely honest. This has become my life, and the student aspect seems like a previous life.”

    William McCormack | william.mccormack@yale.edu  

    Charlotte Zimmer | charlotte.zimmer@yale.edu

  3. With data from NBA study, FDA extends Emergency Use Authorization to Yale’s SalivaDirect COVID-19 test

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    On Saturday morning, the U.S. Food and Drug Administration (FDA) granted an Emergency Use Authorization for SalivaDirect, a saliva-based test for COVID-19 developed by researchers at the Yale School of Public Health.

    The EUA paves the way for other labs that hope to begin use of the test, noted for being inexpensive to produce and implement, with the general public. 

    In mid-May, the NBA approached the Yale team behind SalivaDirect, curious about a potential partnership that could help validate their new saliva-based assay. The collaboration generated a plan to verify the test, as players from 22 of the NBA’s 30 teams embarked on their own experiment to recreate the season in a bubble.

    Now, with the NBA-Yale study ongoing and basketball back in action, both experiments are proving successful. The test will now be rolled out this week, according to Anne Wyllie, the associate research scientist in epidemiology who helped spearhead this research at Yale.

    A non-peer-reviewed preprint published earlier this month by lead researchers Wyllie and Nathan Grubaugh, an assistant professor of epidemiology, found the test to be “highly sensitive” with “high agreement” in testing outcomes when compared to widely used ThermoFisher Scientific nasopharyngeal (NP) swabs. The test is validated for use with reagents and instruments from multiple vendors, which researchers hope will minimize supply chain bottlenecks.

    “Providing this type of flexibility for processing saliva samples to test for COVID-19 infection is groundbreaking in terms of efficiency and avoiding shortages of crucial test components like reagents,” FDA Commissioner Stephen Hahn said in an official release.

    Other saliva tests approved by the FDA, like one developed by Rutgers, are far more expensive than SalivaDirect. In May, Vault Health was offering the test, conducted in a patient’s home with telehealth video supervision, for $150. According to the August SalivaDirect preprint, reagents for the test could cost as little as $1.29 to $4.37 per sample. Researchers estimate that Proteinase K, used for sample processing, would cost somewhere between 13 and 26 cents a sample. Primers and probes would cost a few cents. And a RT-qPCR kit would require between 75 cents and $2.11 per sample.

    When labs offer tests to the public, each test should only cost $10 or less, Wyllie wrote in an email to the News. From the beginning, researchers have sought an inexpensive, flexible test that could be scaled and immune to bottlenecks.

    “We’ve called it SalivaDirect because of the idea that we’re almost testing saliva directly. We’re doing a very simple intermediate treatment,” Wyllie told the News in June. “That makes it a lot cheaper and makes it a lot more high throughput and faster turnaround.”

    The SalivaDirect sampling process, as shown on the team’s website (Graphic: Courtesy of Anne Wyllie, diagram made using BioRender)

    The NBA study allows researchers to validate the test in an asymptomatic cohort, Wyllie said. In addition to receiving daily testing to ensure that they have not contracted the virus, a group of players, coaches and staff heading for the NBA’s Florida bubble volunteered to offer a saliva test sample that researchers could use to verify the efficacy of SalivaDirect.

    Although she could not yet report on the study itself, Wyllie pointed out that the very success of the NBA bubble in Florida has created a unique challenge for researchers studying a new coronavirus test: there are no positive cases. Before teams entered the bubble at Disney World, 25 of 351 players tested positive for the virus between June 23 and July 2. But of the more than 340 players still receiving constant tests within the bubble, zero positive tests have been recorded over the past month, according to official NBA releases.

    An NBA spokesperson did not respond to an immediate request for comment Saturday on whether the league now plans to begin using SalivaDirect in its normal testing regimen. The NBA and National Basketball Players Association contributed more than $500,000 to fund the validation study for SalivaDirect, ESPN reported Saturday. The researchers’ preprint also lists the Huffman Family Donor Advised Fund, George Mason’s Mercatus Center, the Yale Institute for Global Health and the Beatrice Kleinberg Neuwirth Fund as funders.

    Grubaugh and Wyllie have both emphasized how saliva testing could change the game for detecting COVID-19. Not only has it been proven in their studies to be equally — if not more — effective as nasopharyngeal swab testing, but it is more comfortable for patients and significantly lowers the risk of infection for healthcare workers administering the tests.

    The FDA also explained in its announcement that SalivaDirect is incredibly versatile, as it does not require a particular collection device. Any sterile container will work. 

    “This test is also unique because it does not require a separate nucleic acid extraction step,” the FDA wrote. “This is significant because the extraction kits used for this step in other tests have been prone to shortages in the past. Being able to perform a test without these kits enhances the capacity for increased testing, while reducing the strain on available resources.”

    While the saliva testing method is generally more straightforward than NP swab testing, one of the potential barriers to widespread use of SalivaDirect will be getting adequate saliva samples, according to Wyllie. She said that the sample is supposed to just be “the normal saliva that naturally pools in your mouth.” Often people think it is more complicated than that, and they sniff or cough to produce saliva, which can sometimes reduce the test’s accuracy.

    Lead researchers Nathan Grubaugh, left, and Anne Wyllie (Photos: Yale School of Public Health)

    Wyllie told the News when the NBA study started that the ultimate goal was not to commercialize SalivaDirect, and that the protocols were already available online to the public. The FDA’s statement explains that Yale will now provide these testing protocols to other labs on an “open source” basis.

    “Our goals and values hold true. There is still no kit and no commercialization,” Wyllie told the News in an email. “The method is available but we have to designate labs who can use it to make sure they follow the requirements exactly — just some oversight. However, it also means that we have a free license for commercial labs — we want to have conversations about them for testing.”

    By following the instructions put out by Wyllie and Grubaugh’s team, these labs will be able to get the necessary materials and easily do the test themselves, according to the FDA. This is made possible by the fact that SalivaDirect does not depend on specific equipment from Yale and can be scaled up at other laboratories.

    Instructions on the Grubaugh Lab’s coronavirus-centric website, CovidTrackerCT.com, simply invite labs to email salivadirect@gmail.com to begin the process alongside a link to a detailed protocol that covers collecting spit — thinking about “favorite foods” or an “upcoming meal” can stimulate saliva production — processing the sample and reporting a result.

    “I think people will move to this quite quickly — we need more tests as screening measures as we continue to reopen,” Wyllie wrote in an email to the News. “With more frequent testing we can get this virus under control. I think people are much more open to saliva than swabs!”

    The Yale team submitted SalivaDirect as a laboratory developed test for FDA EUA on July 14, 2020, making SalivaDirect the fifth saliva sample test that the FDA has authorized.

    William McCormack | william.mccormack@yale.edu  

    Charlotte Zimmer | charlotte.zimmer@yale.edu