Posted on by Dr. Francis Collins
The coronavirus disease 2019 (COVID-19) pandemic has truly been an all-hands-on-deck moment for the nation. Among the responders are many with NIH affiliations, who are lending their expertise to deploy new and emerging technologies to address myriad research challenges. That’s certainly the case for the dedicated team from the National Institute of Allergy and Infectious Diseases (NIAID) at the NIH 3D Print Exchange (3DPX), Rockville, MD.
A remarkable example of the team’s work is this 3D-printed physical model of SARS-CoV-2, the novel coronavirus that causes COVID-19. This model shows the viral surface (blue) and the spike proteins studded proportionally to the right size and shape. These proteins are essential for SARS-CoV-2 to attach to human cells and infect them. Here, the spike proteins are represented in their open, active form (orange) that’s capable of attaching to a human cell, as well as in their closed, inactive form (red).
The model is about 5 inches in diameter. It takes more than 5 hours to print using an “ink” of thin layers of a gypsum plaster-based powder fused with a colored binder solution. When completed, the plaster model is coated in epoxy for strength and a glossy, ceramic-like finish. For these models, NIAID uses commercial-grade, full-color 3D printers. However, the same 3D files can be used in any type of 3D printer, including “desktop” models available on the consumer market.
Darrell Hurt and Meghan McCarthy lead the 3DPX team. Kristen Browne, Phil Cruz, and Victor Starr Kramer, the team members who helped to produce this remarkable model, created it as part of a collaboration with the imaging team at NIAID’s Rocky Mountain Laboratories (RML), Hamilton, MT.
The RML’s Electron Microscopy Unit captured the microscopic 3D images of the virus, which was cultured from one of the first COVID-19 patients in the country. The unit handed off these and other data to its in-house visual specialist to convert into a preliminary 3D model. The model was then forwarded to the 3DPX team in Maryland to colorize and optimize in preparation for 3D printing.
This model is especially unique because it’s based exclusively on SARS-CoV-2 data. For example, the model is assembled from data showing that the virus is frequently oval, not perfectly round. The spike proteins also aren’t evenly spaced, but pop up more randomly from the surface. Another nice feature of 3D printing is the models can be constantly updated to incorporate the latest structural discoveries.
That’s why 3D models are such an excellent teaching tools to share among scientists and the public. Folks can hold the plaster virus and closely examine its structure. In fact, the team recently printed out a model and delivered it to me for exactly this educational purpose.
In addition to this complete model, the researchers also are populating the online 3D print exchange with atomic-level structures of the various SARS-CoV-2 proteins that have been deposited by researchers around the world into protein and electron microscopy databanks. The number of these structures and plans currently stands at well over 100—and counting.
As impressive as this modeling work is, 3DPX has found yet another essential way to aid in the COVID-19 fight. In March, the Food and Drug Administration (FDA) announced a public-private partnership with the NIH 3D Print Exchange, Department of Veterans Affairs (VA) Innovation Ecosystem, and the non-profit America Makes, Youngstown, OH . The partnership will develop a curated collection of designs for 3D-printable personal protective equipment (PPE), as well as other necessary medical devices that are in short supply due to the COVID-19 pandemic.
You can explore the partnership’s growing collection of COVID-19-related medical supplies online. And, if you happen to have a 3D printer handy, you could even try making them for yourself.
 FDA Efforts to Connect Manufacturers and Health Care Entities: The FDA, Department of Veterans Affairs, National Institutes of Health, and America Makes Form a COVID-19 response Public-Private Partnership (Food and Drug Administration)
Coronavirus (COVID-19) (NIH)
NIH 3D Print Exchange (National Institute of Allergy and Infectious Diseases/NIH, Rockville, MD)
Rocky Mountain Laboratories (NIAID/NIH, Hamilton, MT)
Department of Veterans Affairs (VA) Innovation Ecosystem (Washington, D.C.)
America Makes (Youngstown, OH)
NIH Support: National Institute of Allergy and Infectious Diseases
Posted on by Dr. Francis Collins
We now know that the immune system of nearly everyone who recovers from COVID-19 produces antibodies against SARS-CoV-2, the novel coronavirus that causes this easily transmitted respiratory disease . The presence of such antibodies has spurred hope that people exposed to SARS-CoV-2 may be protected, at least for a time, from getting COVID-19 again. But, in this post, I want to examine another potential use of antibodies: their promise for being developed as therapeutics for people who are sick with COVID-19.
In a recent paper in the journal Science, researchers used blood drawn from a COVID-19 survivor to identify a pair of previously unknown antibodies that specifically block SARS-CoV-2 from attaching to human cells . Because each antibody locks onto a slightly different place on SARS-CoV-2, the vision is to use these antibodies in combination to block the virus from entering cells, thereby curbing COVID-19’s destructive spread throughout the lungs and other parts of the body.
The research team, led by Yan Wu, Capital Medical University, Beijing, first isolated the pair of antibodies in the laboratory, starting with white blood cells from the patient. They were then able to produce many identical copies of each antibody, referred to as monoclonal antibodies. Next, these monoclonal antibodies were simultaneously infused into a mouse model that had been infected with SARS-CoV-2. Just one infusion of this combination antibody therapy lowered the amount of viral genetic material in the animals’ lungs by as much as 30 percent compared to the amount in untreated animals.
Monoclonal antibodies are currently used to treat a variety of conditions, including asthma, cancer, Crohn’s disease, and rheumatoid arthritis. One advantage of this class of therapeutics is that the timelines for their development, testing, and approval are typically shorter than those for drugs made of chemical compounds, called small molecules. Because of these and other factors, many experts think antibody-based therapies may offer one of the best near-term options for developing safe, effective treatments for COVID-19.
So, what exactly led up to this latest scientific achievement? The researchers started out with a snippet of SARS-CoV-2’s receptor binding domain (RBD), a vital part of the spike protein that protrudes from the virus’s surface and serves to dock the virus onto an ACE2 receptor on a human cell. In laboratory experiments, the researchers used the RBD snippet as “bait” to attract antibody-producing B cells in a blood sample obtained from the COVID-19 survivor. Altogether, the researchers identified four unique antibodies, but two, which they called B38 and H4, displayed a synergistic action in binding to the RBD that made them stand out for purposes of therapeutic development and further testing.
To complement their lab and animal experiments, the researchers used a particle accelerator called a synchrotron to map, at near-atomic resolution, the way in which the B38 antibody locks onto its viral target. This structural information helps to clarify the precise biochemistry of the complex interaction between SARS-CoV-2 and the antibody, providing a much-needed guide for the rational design of targeted drugs and vaccines. While more research is needed before this or other monoclonal antibody therapies can be used in humans suffering from COVID-19, the new work represents yet another example of how basic science is expanding fundamental knowledge to advance therapeutic discovery for a wide range of health concerns.
Meanwhile, there’s been other impressive recent progress towards the development of monoclonal antibody therapies for COVID-19. In work described in the journal Nature, an international research team started with a set of neutralizing antibodies previously identified in a blood sample from a person who’d recovered from a different coronavirus-caused disease, called severe acute respiratory syndrome (SARS), in 2003 . Through laboratory and structural imaging studies, the researchers found that one of these antibodies, called S309, proved particularly effective at neutralizing the coronavirus that causes COVID-19, SARS-CoV-2, because of its potent ability to target the spike protein that enables the virus to enter cells. The team, which includes NIH grantees David Veesler, University of Washington, Seattle, and Davide Corti, Humabs Biomed, a subsidiary of Vir Biotechnology, has indicated that S309 is already on an accelerated development path toward clinical trials.
In the U.S. and Europe, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership, which has brought together public and private sector COVID-19 therapeutic and vaccine efforts, is intensely pursuing the development and testing of therapeutic monoclonal antibodies for COVID-19 . Stay tuned for more information about these potentially significant advances in the next few months.
 Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region. Wajnberg A , Mansour M, Leven E, Bouvier NM, Patel G, Firpo A, Mendu R, Jhang J, Arinsburg S, Gitman M, Houldsworth J, Baine I, Simon V, Aberg J, Krammer F, Reich D, Cordon-Cardo C. medRxiv. Preprint Posted May 5, 2020.
 A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Wu Y. et al., Science. 13 May 2020 [Epub ahead of publication]
 Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Pinto D, Park YJ, Beltramello M, Veesler D, Cortil D, et al. Nature. 18 May 2020 [Epub ahead of print]
 Accelerating COVID-19 therapeutic interventions and vaccines (ACTIV): An unprecedented partnership for unprecedented times. Collins FS, Stoffels P. JAMA. 2020 May 18.
Coronavirus (COVID-19) (NIH)
Monoclonal Antibodies (National Cancer Institute/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences