Confronting COVID-19 head on at the Wyss Institute

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Harvard’s Wyss Institute is leveraging its unique technology innovation capabilities to develop diagnostic, therapeutic, and vaccine interventions for COVID-19 at lightning speed.

I was invited to share with you how we at the Wyss Institute for Biologically Inspired Engineering at Harvard University (MA, USA) have been able to rapidly pivot our research and development activities to bring full force to bear on the COVID-19 challenge over the past few months.  We are all acutely aware how the COVID-19 pandemic took the world by surprise at the beginning of 2020, and the global wave of SARS-CoV-2 viral infections that resulted. Here in Boston, the incidence of newly detected infections started to spike in late February, and by the second week of March, Harvard University notified us that we must phase down all research operations except for those directly focused on COVID-19 related activities. Although none of our faculty or staff worked on coronaviruses, we were able to immediately refocus our know-how and various innovative approaches previously developed for other applications to engineer badly needed personal protective equipment (PPE), diagnostics, vaccines, and therapeutics for COVID-19.

We started with 38 team members on site, and we now have almost twice that number working at the main Wyss Institute site in the center of Harvard’s Longwood Medical Area. Because of the Institute’s unique technology translation model, the novel make-up of our community that includes staff members with prior industrial product development experience, and being structured as an independent administrative unit inside Harvard that operates independently of schools or departments and involves multiple other collaborating institutions [1], we have been able to make major advances in all these areas. Some of these technology solutions have already been commercialized and are currently being used to assist healthcare workers in local hospitals across the United States and around the world.

Personalized Protective Equipment

The first wave of attack by the SARS-CoV-2 virus came on so quickly in Boston that clinicians in the trenches feared that their diagnostic laboratories would soon become overwhelmed by patients. As the major Harvard-affiliated hospitals are collaborating institutions of the Wyss Institute, clinicians at these sites who were aware of our technology innovation capabilities immediately reached out for help.

One of the first challenges identified was an acute shortage of PPE, and one of our Wyss faculty member, Jennifer Lewis, along with a senior Wyss staff scientist, James Weaver, refocused their extensive experience in digital fabrication to manufacture face shields. By late March, they were able to quickly come up with a solution, and their team ultimately manufactured and hand-delivered over 1000 of these face shields to Boston Medical Center and St. Vincent’s Hospital Worcester (both MA, USA), which faced desperate PPE shortages [2]. Lewis and Weaver were also enlisted to lead the Face Shield Working Group of the Massachusetts General-Brigham/Partners (MGB/Partners) COVID-19 Innovation Center, which helped to orchestrate efforts being explored by multiple teams in academia and industry across the Boston-Cambridge region to help meet this challenge on an even larger scale. By early April, the team had come up with a series of face shield designs that could meet the diverse needs of the local medical community and partnered with a local manufacturer who could mass produce these designs at ~100,000 units per day, and at very low cost (~60 cents per shield).  Weaver also worked with Harvard’s Graduate School of Design and clinicians at Boston Children’s Hospital and Beth Israel Deaconess Medical Center to design N-95 mask alternatives, ergonomic accessories for surgical masks and intubation shields, which are being used and evaluated by these teams.

Another Wyss core faculty member, Jim Collins, and his team are looking to the future by designing face masks that not only prevent transmission of virus, but also detect when virus capture has occurred by changing color to alert the patient or clinicians to the presence of the SARS-CoV-2 virus. Virus surveillance is carried out by repurposing a synthetic biology approach he developed for paper-based diagnostics [3], in which freeze-dried, cell-free reactions integrated into the face mask textile material are able to detect the viral nucleic acid with a sensitivity approaching that of laboratory diagnostics. If this type of mask were worn, for example, by elderly in nursing homes, it could help to stop the uncontrolled spread of infection and alleviate the burden of overworked healthcare staff.

Nasopharyngeal swabs

Because of the experience of our faculty and staff in working on problem-focused challenges and crossing the academic interface, we have been able to make progress at an incredibly rapid pace. In mid-March, Ramy Arnaout, associate director of the Clinical Microbiology Laboratories at Beth Israel Deaconess Medical Center in Boston (MA, USA) reached out to me and other members of our community for help to obtain replacements for nasopharyngeal (NP) swabs used to collect mucus samples for PCR-based COVID-19 diagnostic testing. Wyss faculty member Kevin Kit Parker co-led a self-organized consortium with Ric Dunlop from 3D printing company Desktop Metals (MA, USA) to develop 3D printed NP swabs, which involved multiple academic labs and 3D printing companies, while relying on Arnaout for clinical testing [4]. This effort resulted in the production of 3D printed NP swab replacements that have been certified in terms of their material properties and clinical usefulness. They also identified five US manufacturers that can collectively produce approximately 4 million NP swabs per week. These products are now commercially available.

When I was approached for help with NP swabs, I had a senior Wyss staff engineer on my team, Richard Novak, begin by 3D printing prototypes and fabricating hand-made swabs. We also reached out to the 3M Company (MN, USA), which we have been collaborating with on a water purification project, to screen off-the-shelf products that could be applied to create the filamentous ‘flocking’ surface coating that is on commercial NP swabs, which is thought to enhance mucus collection.

Within one week, our team had 3D printed various simplified designs that all passed pre-clinical testing for PCR compatibility done by our clinician collaborators. But given the progress made by the other 3D printing teams, we shifted our efforts to focus on manufacturability and cost by designing a single piece (unflocked) swab and exploring manufacturing using injection molding processes that are much higher throughput, lower cost, and available world-wide. This was an important path to follow because injection molding could circumvent supply chain issues that were emerging as we worked.  Novak was also enlisted by the MGB/Partners COVID-19 Innovation Center to lead its Swab Working Group that coordinated efforts of multiple teams working towards this common goal across the Boston-Cambridge ecosystem.

We received our first injection molded prototypes from a local prototyping company by the beginning of April, which our clinical collaborators confirmed to be compatible with the PCR testing.  NP swab designs were iterated and optimized over the next few weeks, and within the month, the final design (which looked much like a small “honey dipper stick”) was shown to pass through all preclinical tests, and users commented that it was more comfortable than the commercial swabs.  At this point, Novak and the team reached out to eight different healthcare centers across the United States and Puerto Rico, and we provided swabs for their evaluation. Wyss staff scientist, David Perry, began to search for commercial medical device manufacturers, packagers, and sterilizers who could help us advance our effort, while Isabel Chico-Calero, who had prior regulatory experience, began to assess our regulatory strategy and contacted the US Food and Drug Administration (FDA) to obtain additional guidance.

We eventually identified a California-based medical device company (IPB, Inc; CA, USA) that agreed to register our swab as an FDA class I exempt medical product, and to manufacture them for clinical use. In the first 2 weeks of May, we had a small initial clinical study carried out with volunteers at TGen North in Arizona (USA), which validated the sample mass collection efficiency of the swabs for PCR analysis.

On 15 May, working through Harvard University, we signed a non-exclusive, royalty free license with IPB to commercialize the swab product.  IPB developed injection molding, packaging, and sterilization capabilities, and they now can manufacture our NP swabs at >1 million per week. Importantly, each sterile NP swab costs less than 70 cents each, which is about half the cost of a commercial NP swab.  At the end of May, we signed a similar license with Papp Plastics (ON, Canada) for production in Canada, Mexico and Colombia, particularly for the hard-hit Latin American markets [5].  We are currently awaiting results of a clinical trial with 300 patients that is being carried out at SUNY Downstate Medical Center in Brooklyn (NY, USA). However, those in need of swabs can now order them from these companies. Finally, given the recent move to do diagnostic testing by sampling the front part of the nose, we have pivoted again to create a shorter nares swab with a similar honey dipper stick end, and we are about to initiate clinical testing with them at multiple clinical centers.

Diagnostics

We at the Wyss Institute continuously benefit from the quality and recognition of our faculty, and one excellent example is David Walt, who was appointed as a member of the National Academies’ Committee on Emerging Infectious Diseases and 21st Century Health Threats, as well as co-leader of the entire MGB/Partners COVID-19 Innovation Center, soon after the pandemic emerged. He also involved two of our senior staff scientists, Rushdy Amad and Pawan Jolly, who lead two of the Center’s key diagnostic working groups. Walt and his research team are also actively working at the Wyss Institute and in his lab at Brigham and Women’s Hospital (another Wyss partner institution) to leverage the SIMOA single molecule detection assay they developed in the past to rapidly create an ultrasensitive SARS-CoV-2 antibody seroconversion assay. In a recent preprint, they described that this assay can detect anti-SARS-CoV-2 antibodies with 86% sensitivity and 100% specificity in patient blood within the first week after infection, and with 100% sensitivity and specificity thereafter, in a first small clinical series [6]. This assay has been used to test healthcare workers at the Brigham and Women’s Hospital, and it was chosen as one of two assays to be evaluated in a Massachusetts Commonwealth population-wide study.  Walt’s team is now also applying this approach to develop multiplexed saliva diagnostics that detect viral RNA, antibodies, and viral antigens in the same sample. He is also working with another Wyss faculty member, George Church, to develop a Next Gen Sequencing-based diagnostic for detecting CoV-2 RNA in saliva, which potentially could enable 10,000 clinical samples to be analyzed in one sequencing run.

Additional diagnostic approaches are being pursued by Peng Yin and Collins, who are independently developing lateral flow point-of-care assays for CoV-2 RNA detection in saliva, which respectively leverage DNA nanotechnology [7] and CRISPR [3] approaches and that offer ultrahigh sensitivity and specificity, as well as simple visual readouts. In addition, Wyss staff scientists Pawan Jolly on my team and Helena de Puig in the Collins group are collaborating on the development of multiplexed, quantitative, point-of-care assays for detection of CoV-2 antibodies in blood and saliva using either paper-based [3] or electrochemical detection [8] methods. These assays will allow simultaneous detection of various antibody types (IgM, IgA, IgG) as well as viral antigens (e.g., spike protein, N protein, etc.) in the same small volume sample with high sensitivity and specificity using either visual or electrical readouts.

Vaccines

Wyss faculty member Dave Mooney is adapting a biomaterials-based cancer vaccine technology he previously developed and licensed to Novartis (Basel, Switzerland) [9] to present SARS-CoV-2 antigens. His team, led by senior staff scientists Mark Cartwright, Ed Doherty, and Mike Super, demonstrated that they can rapidly (within 3 days) fabricate a modular SARS-CoV-2 vaccine using various CoV-2 antigens that generates robust SARS-CoV-2 specific IgG antibody titers in mice. Importantly, these antibodies exhibit high levels of neutralization of a SARS-CoV-2 pseudovirus, and they will soon be testing whether this vaccine can neutralize native SARS-CoV-2 virus as well.

Therapeutics

Multiple Wyss teams are developing novel therapeutics or repurposing existing FDA-approved drugs. The Collins group is developing oligonucleotide-based therapeutics for prevention of COVID-19, which have demonstrated potent inhibitory activity against related coronaviruses in vitro. Wyss faculty member Pam Silver is developing high throughput screens to determine virus effects on the innate immune system, which can be leveraged by other Institute teams. In addition, the Church team is developing computationally-designed therapeutic antibodies that target the novel CoV-2 spike protein, which could offer an entirely different approach to prevent and potentially treat infection.

My group is developing various types of COVID-19 interventions, including RNA therapeutics that enhance host response to viral infection, which we have found to potently inhibit infection of cells by infectious SARS-CoV-2, as well as by related coronaviruses and influenza. If validated in animal studies, this could become a broad spectrum therapeutic, which may be helpful to combat new viral threats that emerge in the future as well as for the current COVID-19 crisis.  We have also applied a novel molecular dynamics simulation pipeline we developed in the past [10] to rationally design drugs that inhibit viral entry by targeting a novel conserved site within the CoV-2 spike protein. Some of first compounds that emerged from this pipeline have shown potent inhibitory activity against SARS-CoV-2 in cell assays. However, our greatest efforts are now focused on leveraging computational algorithms and our human Organ Chip microfluidic culture devices to identify and test FDA-approved drugs that could be repurposed to prevent or treat COVID-19, with major support from the Defense Advanced Research Projects Agency (DARPA) [11].

The Wyss Institute has developed various computational pipelines that harness the power of machine learning, network analysis and data analytics in combination with transcriptomics data to rapidly identify existing FDA-approved drugs that may be repurposed for different disease applications. We have used this approach, for example, to identify existing drugs that can reversibly shut down metabolism and induce a state of ‘suspended animation’ in swimming tadpoles [12] or normalize behavioral abnormalities in a mouse autism model. In the DARPA COVID-19 effort, we are now using these algorithms to identify FDA-approved drugs that are predicted to have COVID-19 therapeutic activity, we will then test them against pseudotyped CoV-2 virus, native SARS-CoV-2 and related coronaviruses in cell based assays, human Organ Chip and in animal models, with the goal of getting drugs into human clinical trials within months rather than years.

This project is an offshoot of another DARPA program that leveraged our human Organ Chip microfluidic culture devices [13] lined by living human lung airway epithelial cells, cultured under air and interfaced with a living pulmonary microvascular endothelium fed by dynamic fluid flow, to help develop potential therapeutics for future influenza pandemics. Prior to the emergence of the COVID-19 crisis, we showed that administration of influenza virus to the airspace of the chip resulted in viral infection and replication, as well as host immune and inflammatory responses, including cytokine production and recruitment of circulating immune cells, which closely mimic responses seen in human patients [14].

When the first article describing the SARS-CoV-2 gene sequence was published in January, my team rapidly engineered a pseudotyped virus expressing the novel CoV-2 spike protein on its surface. We quickly confirmed that it can infect cells from an established cell line often used by virologists, and that multiple FDA-approved drugs, including chloroquine, can inhibit viral entry in these cells. However, when we tested the same drugs in the human Lung Chips and administered them under flow at a clinically relevant dose (Cmax previously measured in human blood), only a subset of these compounds demonstrated inhibitory activity. Interestingly, while chloroquine inhibited viral entry in the cell line as others found with native SARS-CoV-2 virus, it was not active in the Lung Chip. With DARPA funding, we have now established a testing funnel that is fed by drug predictions from our computational algorithms, and involves initial testing with established cell lines using native CoV-2 virus as well as experiments with human Lung and Intestine Chips to assess inhibition of viral infection as well as suppression of clinically important human host inflammatory responses. Down-selected drugs will be tested in animal models with the infectious SARS-CoV-2 virus, and we will try to move the most active agents into human clinical trials as quickly as possible.

Conclusions

The COVID-19 crisis is unique in terms of the extent to which it has impacted the lives of everyone across our entire planet. The research and clinical communities have been impressive in their ability to rally their forces to take on this scourge using all of the tools that can be brought into play. This article provides a window into what we have been able to accomplish at the Wyss Institute, which has been made possible by the unusual organizational structure and innovation model we have developed over the past decade [1]. Central to our approach is a focus on solving problems and ensuring that breakthroughs made at the lab bench leave the lab, which requires providing special support and encouragement for entrepreneurship and commercialization and nurturing creative freedom. By incorporating within our academic community staff, scientists and engineers with extensive product development experience from prior positions in industry or startups, as well as dedicated business development staff who work alongside students, fellows and faculty, we are able to take the shortest path towards impact. In this manner, we combine the best of both worlds, from academia and industry, which provides us with an agility that truly came to the fore in confronting the COVID-19 challenge.  I hope that other institutions explore novel innovation models of their own because it comes in handy in a crisis.

Click here to learn more about the Wyss Institute’s response to COVID-19 >>>

Don IngberDonald E Ingber (MD, PhD): Donald Ingber is the Founding Director of the Wyss Institute for Biologically Inspired Engineering at Harvard University, Professor of Vascular Biology at the Vascular Biology Program and Department of Surgery, Boston Children’s Hospital & Harvard Medical School, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

References

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  12. The Harvard Crimson. Wyss biostasis project succeeds in ‘stopping biological time’ in tadpoles
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Disclaimer

The opinions expressed in this Editorial are those of the author and do not necessarily reflect the views of Infectious Diseases Hub or Future Science Group.

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