Category: Coronavirus

COVID-19 vaccine with IPD nanoparticles wins full approval abroad

• Clinical testing found the vaccine outperforms Oxford/AstraZeneca’s

• The protein-based vaccine, now called SKYCovione, does not require deep freezing

• University of Washington to waive royalty fees for the duration of the pandemic

• South Korea to purchase 10 million doses for domestic use

A vaccine for COVID-19 developed at the University of Washington School of Medicine has been approved by the Korean Ministry of Food and Drug Safety for use in individuals 18 years of age and older. The vaccine, now known as SKYCovione, was found to be more effective than the Oxford/AstraZeneca vaccine sold under the brand names Covishield and Vaxzevria.

SK bioscience, the company leading the SKYCovione’s clinical development abroad, is now seeking approval for its use in the United Kingdom and beyond. If approved by the World Health Organization, the vaccine will be made available through COVAX, an international effort to equitably distribute COVID-19 vaccines around the world. In addition, the South Korean government has agreed to purchase 10 million doses for domestic use.

The Seattle scientists behind the new vaccine sought to create a ‘second-generation’ COVID-19 vaccine that is safe, effective at low doses, simple to manufacture, and stable without deep freezing. These attributes could enable vaccination at a global scale by reaching people in areas where medical, transportation, and storage resources are limited.

“We know more than two billion people worldwide have not received a single dose of vaccine,” said David Veesler, associate professor of biochemistry at UW School of Medicine and co-developer of the vaccine. “If our vaccine is distributed through COVAX, it will allow it to reach people who need access.”

The University of Washington is licensing the vaccine technology royalty-free for the duration of the pandemic.

Clinical trial results

A multinational Phase 3 trial involving 4,037 adults over 18 years of age found that the vaccine, now called SKYCovione, elicits roughly three times more neutralizing antibodies than the Oxford/AstraZeneca vaccine Covishield/Vaxzevria. In these studies, SKYCovione or Covishield/Vaxzevria was administered twice with an interval of four weeks.

In addition, the ‘antibody conversion rate’, which refers to the proportion of subjects whose virus-neutralizing antibody level increased fourfold or more after vaccination, was higher with SKYCovione. According to data collected by SK bioscience, 98 percent of subjects achieved antibody conversion, compared to 87 percent for the control vaccine.

Among study participants 65 years of age or older, the antibody conversion rate of those vaccinated with SKYCovione was over 95 percent, which was a significant difference compared to the control vaccine (about 79 percent for the elderly), raising the expectation that SKYCovione can be used effectively to protect the elderly.

The Phase 3 trial also found that T cell activation levels, which help protect the body from COVID-19, were similar or higher with SKYCovione.

Phase 1/2 trial results announced by SK bioscience last November and posted as a preprint found that SKYCovione was safe and produced virus-neutralizing antibodies in all trial participants receiving the adjuvanted vaccine. In the Phase 3 trial, there were again no serious adverse reactions to the vaccine.

How the vaccine works

Unlike the earliest approved vaccines for COVID-19 that make use of mRNA, viral vectors, or an inactivated virus, SKYCovione is made of proteins that form tiny particles studded with fragments of the pandemic coronavirus. These nanoparticles were designed by scientists at UW Medicine and advanced into clinical trials by SK bioscience and GlaxoSmithKline with financial support from the Coalition for Epidemic Preparedness Innovations. SKYCovione includes GlaxoSmithKline’s pandemic adjuvant, AS03.

“This vaccine was designed at the molecular level to present the immune system with a key part of the coronavirus spike protein. We know this part, called the receptor-binding domain, is targeted by the most potent antibodies,” said Neil King, an assistant professor of biochemistry at UW Medicine and co-developer of the vaccine.

Two laboratories in the UW Medicine Department of Biochemistry led the initial development of the protein-based vaccine: the King Lab pioneered the vaccine’s self-assembling protein nanoparticle technology while the Veesler Lab identified and integrated a key fragment of the SARS-CoV-2 Spike protein onto the nanoparticles.

Years in the making

David Veesler, an assistant professor and HHMI investigator at UW Medicine, has been studying coronaviruses since 2015. Using advanced electron microscopes, researchers in the Veesler lab were the first to identify how the novel coronavirus enters human cells. They were also among the first to report, in Cell, detailed structural information about the virus’ spike protein, a critical piece of its infectious machinery.

In 2016, scientists in the King lab at the UW Medicine Institute for Protein Design began developing a strategy for building a new type of vaccine. They designed proteins that self-assemble into precise spherical particles and later showed that these nanoparticles could be decorated with proteins from a virus. 

Researchers from the two labs worked together in the earliest months of the COVID-19 pandemic to design a protein nanoparticle decorated with 60 copies of the Spike protein receptor-binding domain. The designed nanostructure mimics the repetitive nature of proteins on the surface of viruses, a property that the immune system responds strongly to.

“In order to focus the antibody response where it matters most, we decided to include in the vaccine only a key fragment of the coronavirus spike protein, known as the receptor-binding domain,” said Veesler. “We are thrilled to see that this strategy paid off and has led to a successful subunit vaccine.”

In initial animal studies reported in late 2020 in Cell, the nanoparticle vaccine was found to produce high levels of virus-neutralizing antibodies at low doses. These antibodies target several different sites on the coronavirus Spike protein, a desirable quality that may enhance protection against future coronavirus variants. 

Further preclinical studies, published in Nature, also showed that the vaccine conferred robust protection and produced a strong B-cell response in non-human primates, which may improve how long the protective effects of the vaccine last.

In a recent preprint, a third dose of the vaccine was found to confer strong protection against the Omicon variant of COVID-19 in animals. SK bioscience will initiate testing third doses in 750 human adults soon.

The role of philanthropy

Development of the vaccine at UW Medicine was supported by the Bill & Melinda Gates Foundation, National Institutes of Health, Pew Charitable Trust, Burroughs Wellcome Fund, Fast Grants, and by gifts from Jodi Green and Mike Halperin, Nicolas and Leslie Hanauer, Rob Granieri, anonymous donors, and other granting agencies, including Open Philanthropy. Support leveraged via The Audacious Project was made possible through the generosity of Laura and John Arnold, Steve and Genevieve Jurvetson, Chris Larsen and Lyna Lam, Lyda Hill Philanthropies, Miguel McKelvey, the Clara Wu and Joe Tsai Foundation, Rosamund Zander and Hansjörg Wyss for the Wyss Foundation, and several anonymous donors.

SK bioscience received support for clinical testing from the Bill & Melinda Gates Foundation and the Center for Epidemic Preparedness (CEPI), which is a global partnership supporting vaccine development to fight pandemics. CEPI, along with the World Health Organization and Gavi, the Vaccine Alliance, are co-leaders of COVAX.

AWS gift supports protein structure prediction and design

Amazon Web Services (AWS), a leading cloud computing platform, is donating server time to the Institute for Protein Design to accelerate research in protein structure prediction and design. Computing credits valued at over $1M will be used to train optimized versions of RoseTTAFold for higher accuracy. The research will also support the ongoing development of novel antivirals, vaccines, and diagnostics, including for COVID-19. Improved versions of RoseTTAFold that result will be freely available to the academic research community through the RosettaCommons. All predicted structures for natural proteins will be made freely available via ModelArchive or another public database.

“The use of machine learning in protein science is one of today’s most promising research frontiers. With this generous gift, AWS is helping our scientists build tools and make discoveries that could transform medicine and more. We are grateful for their support,” said Lance Stewart, Chief Strategy and Operations Officer at the Institute for Protein Design.

 

 

COVID-19 vaccine with IPD nanoparticles seeks full approval

The vaccine, now called SKYCovione, is a tiny ball of protein studded with 60 copies of the SARS-CoV-2 receptor-binding domain (shown in red). Image: Ian C Haydon / UW Medicine Institute for Protein Design

A COVID-19 vaccine developed at the University of Washington School of Medicine has proven safe and effective in late-stage clinical testing. SK bioscience, the company leading the vaccine’s clinical development abroad, is seeking full approval for its use in South Korea and beyond.

If approved by regulators, the vaccine will be made available through COVAX, an international effort to equitably distribute COVID vaccines around the world. In addition, the Korean government has agreed to purchase 10 million doses for domestic use.

The Seattle scientists behind the new vaccine sought to create a ‘second-generation’ COVID-19 vaccine that is safe, effective at low doses, simple to manufacture, and stable without deep freezing. These attributes would enable vaccination at a global scale by reaching people in areas where medical, transportation, and storage resources are limited.

“We know we have more than two billion people worldwide that have not received a single dose of vaccine,” said David Veesler, associate professor of biochemistry at UW School of Medicine and co-developer of the vaccine. “If our vaccine is distributed through COVAX, it will allow it to reach these people that need to have access to doses.”

The University of Washington is licensing the vaccine technology royalty-free for the duration of the pandemic.

From SK: SK bioscience and GSK’s Adjuvanted COVID-19 Vaccine Candidate Meets Coprimary Objectives in a Phase III Study; Biologics License Application Submitted for SKYCovione™(GBP510/GSK adjuvant) in South Korea

Clinical trial results

A multinational Phase 3 trial involving 4,037 adults over 18 years of age found that the vaccine, now called SKYCovione, elicits roughly three times more protective antibodies than the Oxford/AstraZeneca vaccine Vaxzevria. In these studies, SKYCovione or Vaxzevria was administered twice with an interval of four weeks.

In addition, the ‘antibody conversion rate’, which refers to the proportion of subjects whose neutralizing antibody level increased fourfold or more after vaccination, was higher with SKYCovione. Ninety-eight percent of subjects achieved antibody conversion, compared to 87 percent for the control vaccine.

Among study participants 65 years of age or older, the antibody conversion rate of those vaccinated with SKYCovione was over 95 percent, which was a significant difference compared to the control vaccine (about 79 percent for the elderly), raising the expectation that SKYCovione can be used effectively to protect the elderly.

The Phase 3 trial also found that T cell activation levels, which help protect the body from COVID-19, were similar or higher with SKYCovione.

Phase 1/2 trial results announced by SK bioscience last November and posted as a preprint last month found that SKYCovione was safe and produced virus-neutralizing antibodies in all trial participants receiving the adjuvanted vaccine. In the Phase 3 trial, there were again no serious adverse reactions to the vaccine.

How the vaccine works

Unlike the earliest approved vaccines for COVID-19 that make use of mRNA, viral vectors, or an inactivated virus, SKYCovione is made of proteins that form tiny particles studded with fragments of the pandemic coronavirus. These nanoparticles were designed by scientists at UW Medicine and advanced into clinical trials by SK bioscience and GlaxoSmithKline with financial support from the Coalition for Epidemic Preparedness Innovations. SKYCovione includes GlaxoSmithKline’s pandemic adjuvant, AS03.

“This vaccine was designed at the molecular level to present the immune system with a key part of the coronavirus spike protein. We know this part, called the receptor-binding domain, is targeted by the most potent antibodies,” said Neil King, an assistant professor of biochemistry at UW Medicine and co-developer of the vaccine.

Two laboratories in the UW Medicine Department of Biochemistry led the initial development of the protein-based vaccine: the King Lab pioneered the vaccine’s self-assembling protein nanoparticle technology while the Veesler Lab identified and integrated a key fragment of the SARS-CoV-2 Spike protein onto the nanoparticles.

Years in the making

David Veesler, an assistant professor and HHMI investigator at UW Medicine, has been studying coronaviruses since 2015. Using advanced electron microscopes, researchers in the Vessler lab were the first to identify how the novel coronavirus enters human cells. They were also among the first to report, in Cell, detailed structural information about the virus’ spike protein, a critical piece of its infectious machinery.

In 2016, scientists in the King lab at the UW Medicine Institute for Protein Design began developing a strategy for building a new type of vaccine. They designed proteins that self-assemble into precise spherical particles and later showed that these nanoparticles could be decorated with proteins from a virus. 

Researchers from the two labs worked together in the earliest months of the COVID-19 pandemic to design a protein nanoparticle decorated with 60 copies of the Spike protein receptor-binding domain. The designed nanostructure mimics the repetitive nature of proteins on the surface of viruses, a property that the immune system responds strongly to.

“In order to focus the antibody response where it matters most, we decided to include in the vaccine only a key fragment of the coronavirus spike protein, known as the receptor-binding domain,” said Veesler. “We are thrilled to see that this strategy paid off and has led to a successful subunit vaccine.”

In initial animal studies reported in late 2020 in Cell, the nanoparticle vaccine was found to produce high levels of virus-neutralizing antibodies at low doses. These antibodies target several different sites on the coronavirus Spike protein, a desirable quality that may enhance protection against future coronavirus variants. 

Further preclinical studies, published in Nature, also showed that the vaccine conferred robust protection and produced a strong B-cell response in non-human primates, which may improve how long the protective effects of the vaccine last.

In a recent preprint, a third dose of the vaccine was found to confer strong protection against the Omicon variant of COVID-19 in animals. SK bioscience will initiate testing third doses in 750 human adults soon.

The role of philanthropy

Development of the vaccine at UW Medicine was supported by the Bill & Melinda Gates Foundation, National Institutes of Health, Pew Charitable Trust, Burroughs Wellcome Fund, Fast Grants, and by gifts from The Audacious Project, Jodi Green and Mike Halperin, Nicolas and Leslie Hanauer, Rob Granieri, anonymous donors, and other granting agencies, including Open Philanthropy.

SK bioscience received support for clinical testing from the Bill & Melinda Gates Foundation and the Center for Epidemic Preparedness (CEPI), which is a global partnership supporting vaccine development to fight pandemics. CEPI, along with the World Health Organization and Gavi, the Vaccine Alliance, are co-leaders of COVAX.

Custom biosensors for detecting coronavirus antibodies in blood

Today we report in Nature Biotechnology the design of custom protein-based biosensors that can detect coronavirus-neutralizing antibodies in blood. This research, which builds on prior sensor design technology developed in the Baker lab, was led by Baker lab postdoctoral scholars Jason Zhang, PhD, and Hsien-Wei (Andy) Yeh, PhD.

From Behind the Paper:

[W]e utilized the de novo designed LOCKR (Latching, Orthogonal Cage/Key pRotein) system as a biosensor for measuring SARS-CoV-2 components and antibodies. The two-state LOCKR system is designed to be switchable, thus ideal for use as a biosensor2. LOCKR contains 2 proteins: 1) Cage protein: contains a 5-helical cage domain tethered to and interacting with the 1-helical latch domain, 2): Key protein: contains the 1-helical key domain that also has affinity to the cage domain. To transform LOCKR into a sensor for SARS-CoV-2 components (specifically the receptor binding domain (RBD) from the spike protein), a de novo designed binder (with picomolar affinity) to RBD called LCB13 was embedded on the end of the latch so that binding of RBD to LCB1 weakens the binding between cage and latch domains, strengthening the binding between cage and key domains, and thus allowing for the 2 LOCKR proteins to associate. To allow for readout of this binding event, split luciferase was added to the LOCKR proteins where the smaller bit was embedded in the latch and the larger portion attached to the end of the key protein. For this RBD sensor, the cage protein is called lucCageRBD and the key protein is called lucKey2. Thus, increased amounts of RBD binding to LCB1 in the cage protein translates to increased bioluminescence from the now reconstituted luciferase.

 

COVID-19 vaccine with IPD nanoparticles meets Phase 1/2 trial goals

This report was written and translated into English by SK bioscience. (Image: SK bioscience)

SK bioscience (CEO Jae-yong Ahn) announced on November 4th that the company has confirmed a positive immune response and safety in the final analysis result of the phase I/II clinical trial of the COVID-19 vaccine candidate, ‘GBP510,’ co-developed with the Institute for Protein Design at the University of Washington in the U.S and adjuvanted with GlaxoSmithKline’s (GSK) pandemic adjuvant system.

SK bioscience enrolled 328 healthy adult participants to conduct the phase I/II clinical trial of GBP510 at 14 clinical institutions including Korea University Guro Hospital. As a result, the generation of the neutralizing antibodies against the COVID-19 virus has been confirmed in all participants receiving the adjuvanted vaccine, demonstrating a 99% seroconversion rate.

The observed neutralizing antibody titer after two weeks from the injection was about 6 times higher in a pseudovirion-based neutralization assay of the entire subject and about 3.6 times higher in a plaque reduction neutralization test of the subset compared to the serum panel of recovered COVID-19 patients. GBP510, which demonstrated a high level of neutralizing antibody induction in the phase I/II clinical trial, which included those over 65 years old whose antibody response rate is usually low, indicated a similar or higher level of immunogenicity compared to the current COVID-19 vaccines.

The result has been acquired by standardized analysis using international standard material and analytic methods established by the World Health Organization and the UK’s National Institute for Biological Standards and Control. The convalescent sera control is inclusive of the lowest to the highest levels of neutralizing antibody formation rates.

In terms of safety, no serious adverse events following immunization were detected in relation to GBP510 injection, demonstrating sufficient tolerability.

SK bioscience will submit the positive data of the phase I/II clinical trial to domestic and international regulatory agencies and plan to further accelerate the development of GBP510 based on the results.

SK bioscience is currently planning to initiate the global phase III clinical trial across the regions including Europe and Southeast Asia, followed by Vietnam where the trial is being already conducted, with the International Vaccine Institute this month. In South Korea, 14 clinical institutions including Korea University Guro Hospital are conducting the phase III clinical trial for GBP510 since August with enrolling about 500 participants, 5 times more population than originally planned.

The protein-based nanoparticle vaccine is studded with 60 copies of the SARS-CoV-2 Spike protein’s receptor-binding domain. Image: IPD

Based on the data from the global phase III clinical trial targeting about 4,000 participants, SK bioscience will prepare to acquire an approval from South Korea’s Ministry of Food and Drug Safety. Also, the company plans to receive WHO Pre-qualification certification and emergency use authorization by individual countries based on the result of the phase III clinical trial.

GBP510 was the first COVID-19 vaccine candidate selected as a part of Wave 2, a project initiated by Coalition for Epidemic Preparedness Innovations (CEPI) in 2020 to support promising vaccine candidates. Following continued positive progress and market authorization, GBP510 will be made available to the COVAX Facility for procurement and equitable allocation worldwide. In addition, SK bioscience will supply GBP510 to the world, including Korea, by establishing its own distribution plans to individual countries through their approval process.

According to Our World in Data, a statistical site developed by a research team at Oxford University in the UK, only about 50% of the world’s population has received at least one dose of a COVID-19 vaccine, and the vaccination rate in low-income countries is only 3.7%, so the demand for vaccinations for COVID-19 is still high.

The synthetic antigen vaccine platform applied to the development of GBP510 allows it to be stored in normal refrigeration conditions under 2 to 8 degrees Celsius, so it can be distributed through the current vaccine logistics network and stored for a long time, securing wider accessibility.

SK bioscience CEO Jaeyong Ahn said, “We were able to successfully manage the phase I/II clinical trial with close cooperation of public health officials including the COVID-19 Pan-government Support Committee, MOHW, MFDS, and the KDCA, as well as global civil and public entities, such as CEPI, Bill and Melinda Gate Foundation, IVI, and GSK. As the phase 3 clinical trial is proceeding smoothly, we will develop GBP510 as quickly as possible to contribute to overcoming the pandemic and securing the right to human health.”

Baker lab joins USAID’s $125M project to detect emerging viruses

To better identify and prevent future pandemics, the University of Washington has become a partner in a five-year global, collaborative agreement with the U.S. Agency for International Development. The newly launched Discovery & Exploration of Emerging Pathogens – Viral Zoonoses, or DEEP VZN project, has approximately $125 million in anticipated funding and will be led by Washington State University.

The effort will build scientific capacity in partner countries to safely detect and characterize viruses which have the potential to spill over from wildlife and domestic animals to human populations.

“The DEEP VZN project provides an exciting chance to better understand why the world is experiencing more frequent and severe outbreaks of zoonotic infectious diseases transmitted between animals and people,” said Dr. Peter Rabinowitz, a co-principal investigator for USAID DEEP VZN and professor of environmental and occupational health sciences in the UW School of Public Health.

“This means gaining knowledge about new viruses that could cause problems in the future, and the ecosystem changes that appear to be driving the process of viruses jumping between species,” Rabinowitz added. “The hope is that this improved understanding will lead to prevention of future pandemics and more resilient ecosystems.”

Rabinowitz is also director of the UW Center for One Health Research and co-director of the UW Alliance for Pandemic Preparedness.

The project plans to initially partner with five countries in Africa, Asia and Latin America to help local organizations carry out large-scale animal surveillance programs within their own countries safely and test samples for viruses using their own laboratory facilities. This will avoid the process of having to ship samples to other countries for testing and build an international network of laboratories capable of quickly responding to disease outbreaks.

“Since the vast majority of viruses that ignite pandemics have their origin in nonhuman animals, it is critical that we figure out which of the many new zoonotic viruses that we are now identifying are most likely to jump species into humans, spread easily from person to person and cause severe disease or death,” said Dr. Judith Wasserheit, a co-principal investigator in the project and chair of the UW Department of Global health.

“The UW Alliance for Pandemic Preparedness focuses on a proactive, integrated systems approach to pandemic preparedness that has brought together internationally recognized leaders in the kinds of laboratory methods that will make it possible for the DEEP VZN team to fully sequence and characterize novel viruses in unprecedented breadth and depth,” said Wasserheit, co-director of the Alliance. “In addition, the Alliance’s approach catalyzed collaborations between these lab-based scientists; One Health leaders working at the interface of human, animal and environmental health; and leaders in Global Health who will work with colleagues in focus countries to identify high-risk locations and subpopulations at the human-animal interface.”

The DEEP VZN project will focus on finding previously unknown pathogens from three viral families that have a large potential for viral spillover from animals to humans: coronaviruses, the family that includes SARS-CoV-2, the virus that causes COVID-19; filoviruses, like Ebola virus; and paramyxoviruses, such as Nipah virus. With 70% of new viral outbreaks in people originating from animals, understanding future threats helps protect the U.S. as well as the partner countries.

The goals are ambitious: to collect over 800,000 samples in the five years of the project, most of which will come from wildlife; then to detect whether known and novel viruses from the target families are present in the samples. When those are found, the researchers will determine their zoonotic potential, or the ability to be transmitted between animals and humans.

This process is expected to yield 8,000 to 12,000 novel viruses, which researchers will then screen and genome sequence for the ones that pose the most risk to animal and human health.

The UW Medicine laboratory effort, led by Dr. Alex Greninger, assistant professor of laboratory medicine and pathology at University of Washington School of Medicine, will use the cutting-edge research expertise of five internationally recognized UW Medicine laboratories to develop innovative techniques and provide reference and support activities for virus detection and characterization by in-country labs.

“It’s time to get to work and find some new viruses. We will be building capacity in other countries to be able to find new viruses and characterize them in hopes to better understand coronaviruses and other viruses circulating in the world,” said Greninger.

The UW Medicine labs:

  • The Greninger Labwill coordinate qRT-PCR and broad serology assay development and in-country training, viral genome recovery and viral glycoprotein characterization.
  • The David Baker Lab will model novel viral glycoproteins to determine risk potential based on in silico screens for potential human receptor affinity.
  • The David Veesler Lab has detailed mechanisms of viral attachment and entry for novel paramyxoviruses and coronaviruses and will extend these biochemical studies to novel viral glycoproteins discovered in DV.
  • The Michael Gale Jr. Lab will determine the degree and mechanisms of innate immunity evasion in human cells by novel viruses.
  • The Van Voorhis Lab will produce recombinant proteins for in-country serological analysis as it has done for SARS-CoV-2.

The UW Department of Global Health will apply its experience in more than 145 countries and expertise in capacity strengthening through the International Training and Education Center for Health, or I-TECH, to support sustainable sampling and strengthen in-country laboratory programs.

In addition to UW and WSU, USAID DEEP VZN includes virology expertise of The Washington University at St. Louis, as well as data management and in-country expertise of public health nonprofits PATH, based in Seattle, and FHI 360, based in North Carolina. These partners have extensive established presence and partners in countries in the target regions.

“To make sure the world is better prepared for these infectious disease events, which are likely to happen more frequently as wild areas become increasingly fragmented, we need to be ready,” said Felix Lankester, lead principal investigator for USAID DEEP VZN and associate professor with WSU’s Paul G. Allen School for Global Health. “We will work to not only detect viruses but also build capacity in other countries, so the United States can collaborate with them in carrying out this important work.”

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This story was adapted by Jake Ellison (UW News) from a Washington State University news release

Two nanoparticle vaccines enter clinical trials

Two different candidate vaccines developed by researchers at the Institute for Protein Design recently entered human clinical trials. GBP510, a candidate COVID-19 vaccine, is undergoing a combined Phase 1/2 trial. Flu-Mos-v1, a candidate mosaic influenza vaccine, is undergoing Phase 1 testing.

Candidate COVID-19 vaccine

Our SARS-CoV-2 vaccine candidate was created with structure-based vaccine design techniques invented in the King lab the IPD. It is based on a computationally designed self-assembling protein nanoparticle that displays 60 copies of a key region of the viral Spike protein.

In preclinical studies reported last year in Cell, the vaccine produced high levels of virus-neutralizing antibodies at low doses. Compared to vaccination with the soluble SARS-CoV-2 Spike protein, on which many leading COVID-19 vaccine candidates are based, the nanoparticle vaccine produced 10 times more neutralizing antibodies in mice, even at a sixfold lower dose. When administered to a single nonhuman primate, it produced neutralizing antibodies targeting multiple different sites on the Spike protein. This may ensure protection against additional mutated strains of the virus, should they arise.

Further preclinical studies, published in Nature, also showed that the vaccine conferred robust protection and produced a strong B-cell response, which may improve how long the protective effects of the vaccine last.

Our lead COVID-19 nanoparticle vaccine candidate is being licensed non-exclusively and royalty-free during the pandemic by the University of Washington. One licensee, Icosavax, a Seattle biotechnology company co-founded in 2019 by King, is currently advancing studies to support regulatory filings and has initiated the U.S. Food and Drug Administration’s Good Manufacturing Practice. To accelerate progress by Icosavax to the clinic, Amgen has agreed to manufacture a key intermediate for these initial clinical studies.

Another licensee, SK bioscience of South Korea, is advancing its own studies to support clinical and further development. Lab studies conducted at SK bioscience offered additional evidence that the nanoparticle vaccine blocked proliferation of the COVID-19 virus.

SK bioscience is working toward commercialization within the first half of 2022 through an expedited approval process, such as an emergency use license. Their eventual goal would be to build up to a manufacturing scale of hundreds of millions of doses per year. GBP510, as SK has named the program, was selected for the first program of the Wave 2 (Next Generation COVID-19 Vaccine) project, which CEPI launched last year to support various COVID-19 vaccine candidates. If GBP510 proves safe and effective and becomes commercialized, it will be supplied globally through the COVAX Facility.

In addition to Neil King, head of vaccine design at the IPD and inventor of the computational design technology used in developing this COVID-19 nanoparticle vaccine candidate, other lead investigators are research scientists Alexandra Walls and Brooke Fiala, and David Veesler, associate professor, all in the University of Washington School of Medicine Department of Biochemistry, who conducted the work along with numerous collaborators.

Mosaic influenza vaccines

IPD researchers, together with collaborators at the National Institutes of Health, have developed experimental flu vaccines that protect animals from a wide variety of seasonal and pandemic influenza strains. The vaccine recently entered Phase 1 clinical testing. If proven safe and effective, these next-generation influenza vaccines may replace current seasonal options by providing protection against many more strains that current vaccines do not adequately cover.

A study detailing how the new flu vaccines were designed and how they protect mice, ferrets, and nonhuman primates was published in Nature. This work was led by researchers at the University of Washington School of Medicine and the Vaccine Research Center part of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

“Most flu shots available today are quadrivalent, meaning they are made from four different flu strains. Each year, the World Health Organization makes a bet on which four strains will be most prevalent, but those predictions can be more or less accurate. This is why we often end up with ‘mismatched’ flu shots that are still helpful but only partially effective,” said lead author Daniel Ellis, a research scientist in the King lab.

To create improved influenza vaccines, the team attached hemagglutinin proteins from four different influenza viruses to custom protein nanoparticles. This approach enabled an unprecedented level of control over the molecular configuration of the resulting vaccine and yielded an improved immune response compared to conventional flu shots. The new nanoparticle vaccines, which contain the same four hemagglutinin proteins of commercially available quadrivalent influenza vaccines, elicited neutralizing antibody responses to vaccine-matched strains that were equivalent or superior to the commercial vaccines in mice, ferrets, and nonhuman primates. The nanoparticle vaccines—but not the commercial vaccines —also induced protective antibody responses to viruses not contained in the vaccine formulation. These include avian influenza viruses H5N1 and H7N9, which are considered pandemic threats.

“The responses that our vaccine gives against strain-matched viruses are really strong, and the additional coverage we saw against mismatched strains could lower the risk of a bad flu season,” said Ellis.

Initial clinical testing of the leading nanoparticle influenza vaccines is expected to take up to two years.

Companion proteins enhance antibody potency

This week we report the design of new proteins that cluster antibodies into dense particles, rendering them more effective. In laboratory testing, such clustered antibodies neutralize COVID-19 pseudovirus, enhance cell signaling, and promote the growth of T cells more effectively than do free antibodies. This new method for enhancing antibody potency may eventually be used to improve antibody-based treatments for a wide range of health disorders.

Antibodies are essential tools in modern medicine, accounting for more than half of all best-selling drugs in recent years. They are used to treat arthritis, cancer, autoimmune disorders, COVID-19, and much more. In 2019, the market for antibody-based technologies reached $150 billion.

Antibodies are typically free-floating proteins. They function by binding to a specific molecular target, which then becomes either activated or inactivated. Virus-neutralizing antibodies that adhere to the surface of the coronavirus can render the pathogen inert. Signaling antibodies that latch onto human cell receptors can alter cellular communication, metabolism, and even gene expression in profound ways.

“We knew that clustering other kinds of signaling proteins can greatly enhance their effects, but there have not been good ways of clustering antibodies,” said lead-author Robby Divine, a graduate student in the department of biochemistry at UW Medicine. Divine led a team of scientists that used molecular design software to create proteins that recognize and bind to specific surfaces that are common to all human antibodies — the so-called fragment crystallizable, or Fc, region.

“Initially, we were just curious to see if we could build proteins that would grab hold of antibodies,” said Divine. With continued bioengineering, the team eventually created proteins that not only bound to antibodies but also assembled them into dense, spherical nanoparticle structures. They call these structures ‘antibody nanocages.’

“Some of the first cages we made would only grab two antibodies per cluster, but we later created cages that could bind six, 12, or even 30. And we quickly found that any antibody we tested could pretty easily be put into a nanocage. It was surprising to see how generic this approach was.”

Lead author Robby Divine, PhD

So far, antibody nanocages have yielded promising results in various laboratory tests. Certain antibodies known to neutralize the COVID-19 coronavirus become seven-fold more potent when formulated into a nanocage. Other antibodies that induce signaling of a protein called CD40 in mammalian cells functioned around 20-fold more potently when formulated into a nanocage, allowing for 20-fold lower dosing to achieve identical signaling results. And when the once-promising anti-cancer antibody conatumumab was formulated into a nanocage, it was able to potently trigger cell death in lab-grown cancer cells. The same antibody alone did not promote cancer cell death, even at the highest concentrations tested. More experiments will be needed to establish whether these trends hold in animal testing.

“The most exciting aspect of this technology is that it is so simple to swap different antibodies into the assemblies. We envision many new treatments emerging from this one common tool,” said senior author David Baker, professor of biochemistry and director of the UW Medicine Institute for Protein Design.

This work was led by UW Medicine and included researchers from the Benaroya Research Institute and Fred Hutchinson Cancer Research Center, Seattle, WA, USA; and Tehran University of Medical Sciences, Tehran, Iran. This work was supported by the National Institutes of Health, National Science Foundation, Howard Hughes Medical Institute, Washington Research Foundation, Audacious Project, Nordstrom-Barrier Directors Fund, Washington State General Operating Fund, Wu Tsai Translational Investigator Fund, Nan Fung Life Sciences Translational Investigator Fund, Fred Hutch COVID-19 Research Fund, a Pew Biomedical Scholars Award, and a Burroughs Wellcome Investigators award.

New sensors detect coronavirus proteins and antibodies

This week we report [PDF] a new way to detect the virus that causes COVID-19, as well as antibodies against it. Scientists at the Institute for Protein Design have created protein-based sensors that glow when mixed with components of the virus or specific antibodies. This breakthrough could enable faster and more widespread testing in the near future.

To diagnose coronavirus infection today, most medical laboratories rely on a technique called RT-PCR, which amplifies genetic material from the virus so that it can be seen. This technique requires specialized staff and equipment. It also consumes lab supplies that are now in high demand all over the world. Supply-chain shortfalls have slowed COVID-19 test results in the United States and beyond.

To directly detect key proteins that make up the coronavirus without the need for genetic amplification, a team led by IPD bioengineering graduate student Alfredo Quijano-Rubio and IPD postdoctoral scholar Hsien-Wei Yeh used Rosetta to design new LOCKR-based biosensors. These protein-based devices can recognize either a target protein from the virus or antibodies, bind to them, then emit light through a biochemical luciferase reaction.

Artist’s depiction of a LOCKR-based SARS-CoV-2 biosensor.

Antibody testing can reveal whether someone has had COVID-19 in the past. It is being used to track the spread of the pandemic, but it too requires complex laboratory supplies and equipment.

The same team of UW researchers also created biosensors that glow when mixed with COVID-19 antibodies. They showed that these sensors do not react to other antibodies that might also be in the blood, including those that target other viruses. This sensitivity is important for avoiding false positives.

“We have shown in the lab that these new sensors can readily detect virus proteins or antibodies in simulated nasal fluid or donated serum. Our next goal is to ensure they can be used reliably in a diagnostic setting. This work illustrates the power of de novo protein design to create molecular devices from scratch with new and useful functions” said David Baker, professor of biochemistry and director of the Institute for Protein Design.

Beyond COVID-19, the team also showed that similar biosensors could be designed to detect medically relevant human proteins such as Her2 and Bcl-2, as well as a bacterial toxin and antibodies against Hepatitis B virus.

This research was supported by the National Institutes of Health, Howard Hughes Medical Institute, Air Force Office of Scientific Research, The Audacious Project, Eric and Wendy Schmidt by recommendation of the Schmidt Futures, Washington Research Foundation, Nordstrom Barrier Fund, The Open Philanthropy Project, LG Yonam Foundation, BK21 PLUS project of Korea, United World Antiviral Research Network (UWARN) one of the Centers Researching Emerging Infectious Diseases, as well as gift support from Gree Real Estate and “la Caixa” Foundation.

Design of an ultrapotent COVID-19 vaccine candidate

Today we report in Cell (PDF) the design and initial preclinical testing of an innovative nanoparticle vaccine candidate for the pandemic coronavirus. It produces virus-neutralizing antibodies in mice at levels ten-times greater than is seen in people who have recovered from COVID-19.

Compared to vaccination with the soluble SARS-CoV-2 Spike protein, which is what many leading COVID-19 vaccine candidates are based on, the new nanoparticle vaccine produced ten times more neutralizing antibodies in mice, even at a six-fold lower vaccine dose. The data also show a strong B-cell response after immunization, which can be critical for immune memory and a durable vaccine effect. When administered to a single nonhuman primate, the nanoparticle vaccine produced neutralizing antibodies targeting multiple different sites on the Spike protein. This may ensure protection against mutated strains of the virus, should they arise.

The vaccine candidate was developed using structure-based vaccine design techniques invented at UW Medicine. It is a self-assembling protein nanoparticle that displays 60 copies of the SARS-CoV-2 Spike protein’s receptor-binding domain in a highly immunogenic array. The molecular structure of the vaccine roughly mimics that of a virus, which may account for its enhanced ability to provoke an immune response.

The lead authors of this paper are Alexandra Walls, a research scientist in the laboratory of David Veesler who is an associate professor of biochemistry at the University of Washington School of Medicine; and Brooke Fiala, a research scientist in the laboratory of Neil King who is an assistant professor of biochemistry at the University of Washington School of Medicine and head of vaccine research at the Institute for Protein Design.

“We hope that our nanoparticle platform may help fight this pandemic that is causing so much damage to our world. The potency, stability, and manufacturability of this vaccine candidate differentiate it from many others under investigation.”

Neil King, PhD, head of vaccine design at the IPD and inventor of the computational vaccine design technology used in this work.

Hundreds of candidate vaccines for COVID-19 are in development around the world. Many require large doses, complex manufacturing, and cold-chain shipping and storage. An ultrapotent vaccine that is safe, effective at low doses, simple to produce and stable outside of a freezer could enable vaccination against COVID-19 on a global scale.

“I am delighted that our studies of antibody responses to coronaviruses led to the design of this promising vaccine candidate,” said Veesler, who spearheaded the concept of a multivalent receptor-binding domain-based vaccine.

The lead vaccine candidate is being licensed non-exclusively and royalty-free during the pandemic by the University of Washington. One licensee, ​Icosavax, Inc.,​ a Seattle biotechnology company co-founded in 2019 by King, is currently advancing studies to support regulatory filings and has initiated the U.S. Food and Drug Administration’s Good Manufacturing Practice (GMP). To accelerate progress by Icosavax to the clinic, A​mgen Inc.​, has agreed to manufacture a key intermediate for these initial clinical studies. Another licensee, S​K bioscience Co., Ltd.​, based in South Korea, is also advancing its own studies to support clinical and further development.

This work was supported by the National Institutes of Health, Bill & Melinda Gates Foundation, gifts from Jodi Green and Mike Halperin and from The Audacious Project, as well as other granting agencies.

Antiviral proteins block coronavirus infection in the lab

Today we report in Science [PDF] the design of small proteins that protect cells from SARS-CoV-2, the virus that causes COVID-19. In experiments involving lab-grown human cells, the activity of the lead antiviral candidate produced (LCB1) was found to rival that of the best-known SARS-CoV-2 neutralizing antibodies. LCB1 is currently being evaluated in rodents. 

Coronaviruses are studded with so-called Spike proteins that latch onto human cells, leading to infection. Drugs that interfere with this process may treat or even prevent infection. Researchers at the IPD used computers to design new proteins that bind tightly to SARS-CoV-2 Spike protein, interfering with its ability to infect cells. Beginning in January, over two million candidate Spike-binding proteins were designed on the computer, and over 118,000 were produced and tested in the lab.

“Although extensive clinical testing is still needed, we believe the best of these computer-generated antivirals are quite promising. They appear to block SARS-CoV-2 infection at least as well as monoclonal antibodies but are much easier to produce and far more stable, potentially eliminating the need for refrigeration.”

Longxing Cao, postdoctoral scholar at the IPD

The researchers created antiviral proteins using two approaches. First, a segment of the ACE2 receptor, which SARS-CoV-2 naturally binds to, was incorporated into a series of small protein scaffolds. Second, completely synthetic proteins were designed from scratch. The latter method produced the most potent antivirals, including LCB1, which is roughly six times more potent on a per mass basis than the most effective monoclonal antibodies reported thus far.

This work was conducted by scientists from the University of Washington School of Medicine and Washington University School of Medicine in St. Louis.

“Our success in designing high-affinity antiviral proteins from scratch is further proof that computational protein design can be used to create promising drug candidates,” said senior author and HHMI Investigator David Baker, director of the IPD.

To confirm that the new antiviral proteins attached to the coronavirus Spike protein as intended, the team collected snapshots of the two molecules interacting using cryo-electron microscopy. These experiments were performed by researchers in the laboratories of David Veesler, assistant professor of biochemistry at the University of Washington School of Medicine, and Michael S. Diamond, the Herbert S. Gasser Professor in the Division of Infectious Diseases at Washington University School of Medicine in St. Louis.

This work was supported by the National Institutes of Health, Defense Advanced Research Projects Agency, The Audacious Project at the Institute for Protein Design, Eric and Wendy Schmidt by recommendation of the Schmidt Futures program, Open Philanthropy Project, an Azure computing resource gift for COVID-19 research provided by Microsoft, and the Burroughs Wellcome Fund.

De novo nanoparticles as vaccine scaffolds

IPD researchers have developed a new vaccine design strategy that could confer improved immunity against certain viruses, including those that cause AIDS, the flu, and COVID-19. Using this technique, viral antigens are attached to the surface of self-assembling, de novo designed protein nanoparticles. This enables an unprecedented level of control over the molecular configuration of the resulting vaccine. This research, which includes collaborative pre-clinical evaluation of initial vaccines in animals, is detailed in three new papers published on August 4.

The first paper, published in the journal eLife, describes the overall vaccine design strategy and how it was used to create vaccine candidates for three important viruses: HIV, RSV, and influenza.

“One of the things we found in this study was that putting the same viral antigen on different nanoparticles alters which regions antibodies can see. This can be used to bias the immune response towards certain regions of an antigen that confer greater protective immunity.” 

George Ueda, lead author and IPD translational postdoctoral scholar.

The second paper, published in PLOS Pathogens, looks at how one of the new HIV vaccine nanoparticles performed in rabbits. A team led by Aleks Antanasijevic and Andrew Ward at Scripps Research found that repeated immunization of the vaccine resulted in a higher proportion of neutralizing antibodies compared to immunization with the same antigen not displayed on the nanoparticle.

The third paper, published in npj Vaccines, looks at how one of the HIV vaccine nanoparticles circulates through the body of rhesus macaques. A team led by Jacob Martin and Darrell Irvine at MIT found that after three days, it became concentrated in lymph node tissues, which is where B cells learn how to fight infection. This may account in part for the observed enhanced immunity.

“Simply injecting an antigen is not necessarily enough to confer a protective immune response. Our goal was to create new protein-based vaccines that mimic the repetitive and spiky shape of a virus because this can drive a more protective immune response. What we found in this study was that the nanoparticle vaccines are also retained better in lymph nodes than antigen alone.” said Ueda.

Relevance for COVID-19

The team chose to focus on HIV, RSV, and influenza because those viruses all contain surface proteins with similar shapes — trimers. The virus that causes COVID-19 also contains a trimeric surface protein. Efforts are now underway at UW Medicine and at the National Institutes of Health Vaccine Research Center to develop nanoparticle vaccines against COVID-19 using this new strategy.

“We have found that the two-component nanoparticles we’ve been designing can be used to improve the potency of antigens from a number of important pathogens, including SARS-CoV-2. We’re convinced that they are a robust and versatile platform for designing nanoparticle vaccines.”

Neil King, head of vaccine design at the IPD.

This collaborative research was led by UW Medicine, Scripps Research, and the Koch Institute for Integrative Cancer Research at MIT. It also included researchers from Cornell University,  Emory University, University of Amsterdam, University of Southampton, the Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, the Lawrence Berkeley Laboratory, and the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

This work was supported by the Bill and Melinda Gates Foundation and the Collaboration for AIDS Vaccine Discovery; the National Institute of Allergy and Infectious Diseases Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, Center for HIV/AIDS Vaccine Development; and by the National Science Foundation; and by The Audacious Project; and by the Howard Hughes Medical Institute. This work was also supported by the European Union’s Horizon 2020 research and innovation program. This work was partially funded by IAVI with the generous support of USAID, Ministry of Foreign Affairs of the Netherlands, and the Bill & Melinda Gates Foundation.

With an emergency meeting, RosettaCommons aims to accelerate COVID-19 research

On the day the number of confirmed global COVID-19 infections crossed one million, a team of over three hundred scientists from around the world kicked off a virtual conference aimed at stopping the virus.

The event was an emergency meeting of member labs from the RosettaCommons, a consortium of over 90 laboratories who together develop and apply Rosetta, a powerful molecular modeling suite. Using this software, scientists have previously created experimental vaccines, candidate antiviral drugs and helped solve the structures of important infectious disease proteins, enabling further drug development. 

As of early April, dozens of RosettaCommons labs had begun research on COVID-19. 

This community of computational biochemists normally gathers in person each summer and winter to share updates and spark new collaborations. Given the urgency of the pandemic, however, an emergency meeting was called by Jeffrey Gray, a RosettaCommons member and professor of chemical and biomolecular engineering at Johns Hopkins. 

“I think our community has much to offer,” said Gray. “We have powerful tools that have led to new technologies and a strong tradition of collaboration. Our work is needed now.”

Computer-generated vaccines

Vaccine design was a major focus of the two-day event. Multiple researchers presented their preliminary efforts to create custom vaccines against SARS-CoV-2, the virus that causes COVID-19. Rosetta’s proven ability to enable the atomically accurate design of custom immunogens [1,2] makes it a powerful tool in the race for an effective vaccine.

Neil King, assistant professor of biochemistry at the University of Washington and member of the Institute for Protein Design (IPD), shared his lab’s efforts to design and test multiple subunit and nanoparticle vaccines. This research, which is among the only work still being done in person at the IPD, is largely supported by the Bill & Melinda Gates Foundation. 

Tim Whitehead, associate professor of chemical and biological engineering at CU Boulder, is using Rosetta to stabilize proteins from SARS-CoV-2, including the spike protein, in hopes of improving their immunogenicity. 

Researchers from Scripps Research and the Wistar Institute also presented their unique efforts to create novel vaccines by design, including strategies for presentation of specific and broadly neutralizing epitopes [3]. 

Designer antivirals

The spike protein from SARS-CoV-2 is “a beast,” noted Eva-Maria Strauch, assistant professor of pharmaceutical and biomedical sciences at the University of Georgia, Athens. Her lab is applying  Rosetta to try to create proteins that could block the coronavirus spike. If successful, these molecules would constitute a new class of antivirals. 

“Each [virus] has its own secrets,” said Strauch, whose initial round of experimental coronavirus antivirals will be tested in the lab soon. Strauch has been researching countermeasures for infectious disease proteins for years, but she said with COVID-19, her academic niche “became pretty real.”

Similar efforts are being persuaded in David Baker’s lab at the IPD. Graduate students Brian Coventry and Buwei Huang presented a new method for designing binders in high throughput. IPD scientist Brian Koepnick also shared how the computer game Foldit is challenging players to come up with their own antiviral designs. Ninety-nine of the most promising solutions from Foldit players will soon be tested for activity in Seattle. 

The Fleichman lab at the Weizmann Institute of Science in Israel is working to automate the design of certain antivirals. Graduate student Jonathan Weinstein shared an update on their efforts to automatically design anti-coronavirus nanobodies. These natural proteins resemble antibodies, but are much smaller, potentially making them easier and cheaper to produce. 

The role of machine learning 

Several labs are applying techniques from machine learning to enhance their research. 

In the Baker lab, graduate student Nao Hiranuma is developing deep learning models that make filtering binders designs two to three times more successful. Coming up with millions of putative binders on the computer is now relatively easy, said Coventry. “Filtering has been the name of the game.” The team aims to test only the most promising candidates, then to use data from high-throughput experiments to guide further rounds of design.

In the Meiler Lab at Vanderbilt University, machine learning techniques are being used to guide the design of SARS-CoV-2 protease inhibitors. Graduate student Benjamin Brown presented an “in-progress algorithm” that he has readapted due to the urgent need to stop COVID-19. 

The power of teamwork

Even in extraordinary times, the RosettaCommons pulls together. Preliminary data and research efforts were shared openly during the conference. Members are also creating lists of resources — reagents, genes and computational methods — to help coordinate global efforts.

The RosettaCommons maintains its commitment to continue communicating and supporting member labs, including a long-standing effort to be inclusive of all people in our work. During the conference, live closed-captioning was donated by Verbit.ai.

5 questions about designing coronavirus vaccines from our Reddit AMA

Researchers from our vaccine design team recently participated in a Reddit ‘Ask Me Anything’ about our SARS-CoV-2 vaccine research. Reddit users asked over a hundred questions by the time the live event ended — we are sorry we could not address them all. 

We were lucky to be joined by Lexi Walls, a postdoctoral scholar in the UW Veesler lab, who recently helped lead an effort to determine the structure of the SARS-CoV-2 spike protein by cyro-electron microscopy. “It was so wonderful to see such a broad audience pour in so many well-thought out questions about our research,” said Erin Yang, a Baker lab graduate student who helped organize the event.

Here is our pick for the top five vaccine-related questions from our Reddit AMA:

If a vaccine was created, and proven to work, how long would it take for it to be mass produced and for it to reach the general public?

The projections of 1 year to 18 months to have an FDA approved vaccine are probably accurate — if some of the vaccine candidates that [are] either in development or about to start clinical trials as of today do in fact provide protection (which we don’t know yet) and everything goes well.

Vaccines, like all medicines, have to be very safe. The safety bar for vaccines is very high as they are administered to large numbers of people. Much of the time that will be required to get a vaccine out will be devoted to ensuring that vaccine candidates are very safe, as well as effective.

— Lauren Carter

Is there a chance we’ll ever develop one day the technology to create and manufacture vaccines for new diseases, quickly enough to tackle their extremely damaging first wave (so essentially have a vaccine ready within 2, 3 months of a disease being discovered)?

Potentially. There will always be a need for safety trials, but new vaccine platforms that are modular (like ours) — once they have been proven in clinical trials — could be developed quickly for new indications. As an example, annual flu vaccines are manufactured relatively rapidly, but there is room for further improvement.  — Lauren Carter

One long-term goal (which will not be ready for this pandemic) would be to create vaccines that could provide universal coverage against any family of viruses that has a high chance of causing a pandemic. For example, one could imagine having a single vaccine that protects against all possible coronaviruses, another vaccine that protects all possible flu viruses, etc. Based on what we know about how the immune system responds to flu, a universal flu vaccine does look possible as there are pieces of flu that are conserved between all flu viruses that infect humans. Coronaviruses are less studied in this regard. Hopefully greater study of them in the coming years will show that such a vaccine could be possible.

— Dan Ellis

What are we seeing in the human antibodies from recovered patients and how does that influence a potential vaccine? Are there other proteins we can target aside from the spike protein? 

There are a variety of proteins present in coronaviruses, but the spike protein is the major vaccine and antibody target because it is present on the outside of virus and is the major protein that our immune systems target during natural infection. The spike protein is also the workhorse of viral entry — the spike protein’s role is to bind to host cells and fuse viral and host membranes to allow for infection. The spike is therefore the first target the immune system sees and acts against. This also means that if we can target antibodies to it, we could prevent viral entry into host cells completely and block infection (which is the ultimate goal!). The most promising target on the spike protein is called the receptor binding domain, the goal being to block the interaction with host (our) receptor. If this interaction is blocked, then the virus cannot enter cells and no infection can occur.

As for what we are seeing from human antibodies from infected patients… this is a pre-print (not yet peer-reviewed- a way to publicly post results early to allow for sharing of knowledge as fast as possible, but submitted to a scientific journal to go through that process) on just that topic!

 — Lexi Walls

What makes creating a vaccine so hard? I genuinely want to understand the work and tech that goes behind creating something that kills a virus.

This is a really complex question, and we’ll only be able to provide a partial answer. If you are curious about how vaccines and drugs are developed, here are a few other resources: https://www.sciencedirect.com/topics/medicine-and-dentistry/vaccine-development

At a very basic level, making vaccines is hard because we don’t fully understand how the immune system perceives pathogens and most effectively marshals its forces (T cells, B cells, etc.) to eliminate pathogens. We know some things, like antibodies and T cells are important. So the job of vaccinologists is to make a thing that stimulates the immune system — which we do not fully understand — in just the right way. You want to raise the right flags for the immune system to see in order to identify the threat, but you don’t want to overwhelm the system or alert it to the wrong thing.

Another challenge in making vaccines is that they must be exceedingly safe. Vaccines are administered to large numbers of healthy people, so they must do no harm. Making a thing that provokes a potent, protective immune response but that is totally safe requires a lot of knowledge, skill, and operational excellence.

Finally, viruses and bacteria are experts at evading the immune system — they have developed lots of tricks to subvert or suppress immune responses. So you have to know enough about the bug (the virus or bacterium or whatever) to teach the immune system how to eliminate it, despite the tricks the bug tries to play.

— Neil King

How many vaccine candidates are there currently? Where are the trials being conducted?

A few different vaccine candidates from other groups have entered the earliest stage of clinical testing, and many others are racing to get there. A handful of patients have been injected in Seattle as part of one mRNA vaccine trial (Phase 1).

This is an incredible moment for science — all hands are on deck, moving quickly but safely.

— Erin Yang

 

Volunteers rally to Rosetta@Home to stop COVID-19

Planetariums, businesses and more are now donating idle computing power to help advance biomedical research. Image: Frost Science

As schools, museums, offices and stores shutter to slow the spread of the new coronavirus, millions of people are now finding themselves stuck at home. Fortunately, even in these trying times, there are are small steps that anyone can be take to help combat COVID-19.

One option is to donate to biomedical research — but doing so doesn’t necessarily require opening your wallet.

Rosetta@Home is a distributed computing project that relies on a network of volunteer computers. The goal of the project is to learn more about important biomolecules, including the proteins that comprise the new coronavirus. In doing so, scientists may discover how to create medicines and vaccines to stop it. Rosetta@Home operates on the Berkeley Open Infrastructure for Network Computing, or BOINC, which has existed since 2002. BOINC is open-source and funded primarily by the National Science Foundation.

In recent days, Rosetta@Home has seen a surge of new volunteers who are generously donating the use of their idle desktop, laptop and smartphone processors. The number of active users has doubled, and four of the project’s ten best compute days have occurred just in the last week. This giving is powering research on the new coronavirus at the UW Institute for Protein Design and at other universities.

New volunteers stepping up

To keep the public safe from the new coronavirus, the Phillip and Patricia Frost Museum of Science in Miami, Floria has had to temporarily close. The museum is home to a state-of-the-art planetarium, powered by the Frost Planetarium’s Dell PowerEdge 7910 servers, consisting of 168 processors. The Frost Museum just announced that it is generously donating its computer downtime to the Rosetta@Home project.

 

Image: Frost Science

“As a leading scientific institution, we wanted to find a way to repurpose the powerful computing technology we had idle with our closure. We are now actively supporting groundbreaking research that will help us solve some of the world’s biggest challenges, such as COVID-19. Now more than ever, we need to work together and keep science and high quality research at the forefront of our thinking. We encourage others to join our Frost Science BOINC team and help make a difference, right from their homes” said Frank Steslow, Frost Science President & CEO.

Modus Create, a multi-national consulting firm, has also announced that it is donating all spare computer parts at its headquarters in Reston, Virginia to both Rosetta@Home and Folding@Home, a similar project. “Humanity’s ingenuity is often best demonstrated at times of crisis,” they write. Like many volunteers, Modus has also created a team on BOINC to organize their giving.  Over 11,000 such teams have been formed, including many from universities, business and other institutions.

It is easy to join Rosetta@Home

Joining Rosetta@Home is simple. First, download the BOINC app on a compatible device (Windows, Mac, Linux or Android). Then, select Rosetta@Home as your preferred project. That’s it! Rosetta@Home is not for profit, operated by academics and will not collect any of your personal information. Follow the project on Twitter for updates: @RosettaAtHome

With Rosetta@Home running on your devices, you can contribute to science even as you sleep.

Play Foldit to help stop coronavirus (VIDEO)

You don’t have to be a scientist to do science! By playing the computer game Foldit, you can help discover new antiviral drugs that might stop the novel coronavirus. The most promising solutions will be manufactured and tested at the University of Washington Institute for Protein Design in Seattle.

Foldit is run by academic research scientists. It is free to play and not-for-profit. To get started, download Foldit on your computer and create a username.

We recommend that new players start with the Foldit Intro Puzzles.
After some practice, move on to the Science Puzzles and try out the Beginner: Coronavirus puzzle.
We also have an advanced coronavirus puzzle where you can try to design an antiviral protein from scratch!

To meet other players, check out the Foldit Discord channels.

Note: Foldit is an interactive computer game and not a distributed computing project. If you would like to donate spare computer time to science, please check out the Rosetta@Home project on BOINC.

To support laboratory testing, please consider making a donation to the Institute for Protein Design at the UW School of Medicine.

Follow Foldit on Twitter.

Rosetta’s role in fighting coronavirus

We are happy to report that the Rosetta molecular modeling suite was recently used to accurately predict the atomic-scale structure of an important coronavirus protein weeks before it could be measured in the lab. Knowledge gained from studying this viral protein is now being used to guide the design of novel vaccines and antiviral drugs.

On January 30, the World Health Organization declared the ongoing coronavirus outbreak (COVID-19, caused by the virus SARS-CoV-2) a public health emergency of international concern. Scientists around the world are racing to learn more about this deadly virus which has already spread to more than 30 countries.

The best predicted structure of the spike protein (blue) closely matches the structure later solved by Cryo-EM (tan).

Importantly, structural biologists are quickly gaining insights into what the proteins that make up this virus look like and how they function.

One viral protein in particular — the spike protein — allows SARS-CoV-2 to fuse its membrane with those on human cells, leading to infection. Researchers at UT Austin this week used cryo-electron microscopy to create the first 3D atomic-scale map of the SARS-CoV-2 spike protein in its prefusion state. Like other viral spike proteins, this spear-like molecule is thought to take on two distinct conformations: one before it infects cells, and a different, ‘post-fusion’ state after. Other groups are also applying similar techniques in their laboratories to learn even more about this critically important protein.

Coronavirus spike proteins — like the proteins found in your body — ‘fold up’ in order to function.

Robetta, our online Rosetta-based protein structure prediction server that is free to use for academics, was able to accurately predict the results of this folding process. In early February, it calculated 3D atomic-scale models of the SARS-CoV-2 spike protein in its prefusion state that closely match those later discovered in the lab.

To download these models, click here.

Designing therapeutics

With this knowledge in hand, researchers at the Institute for Protein Design are now working to create new proteins to neutralize coronavirus. If successful, these antiviral proteins would stick to the SARS-CoV-2 spike protein and thereby prevent viral particles from infecting healthy cells.

A de novo miniprotein binder (pink) designed to bind to the SARS-CoV-2 spike protein.

These new drug candidates — a type of molecule we call ‘mini-protein binders’ — seek to combine the specificity of antibodies with the high stability and manufacturability of small molecule drugs. Mini-protein binders are custom-designed on the computer to adhere only to specific targets, such as specific grooves on the SARS-CoV-2 spike protein.

In 2017 we first reported our high-throughput mini-protein binder design strategy. Together with colleagues we designed and tested over 22,000 mini-proteins that target influenza and botulinum neurotoxin B, along with over 6,000 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. 

The de novo designed mini-protein binders produced in that study exhibited much greater stability at elevated temperatures and better neutralization in animal models than comparable antibodies and natural protein derivatives. Probably as a result of their small size and very high stability, they also elicited little immune response. The best of the flu-targeting designs provide prophylactic (before infection) and therapeutic (after infection) protection against influenza infection in mouse models with a potency rivaling or surpassing that of antibodies.

Our researchers are now designing on the computer tens of thousands of anti-coronavirus mini-protein binders. In the coming weeks we hope to produce these mini-proteins in the lab and measure their ability to bind to spike protein. Following this, much more laboratory testing would still be needed to evaluate the safety and efficacy of these experimental coronavirus drugs.

Designing coronavirus vaccines

Technology developed in the King Lab at the Institute for Protein Design is also being applied to try to create an effective vaccine against SARS-CoV-2.

This experimental SARS-CoV-2 vaccine was made by fusing multiple copies of the coronavirus spike protein (red) to the outside of a designed protein nanoparticle (orange and gray).

Our colleagues in the Veesler Lab in UW Biochemistry and at the Vaccine Research Center at the National Institutes of Health have fused coronavirus spike proteins to the outside of Rosetta-designed protein nanoparticles to form self-assembling vaccine candidates. Some of these are currently being evaluated in mice. This work builds off our recent efforts to create respiratory vaccines by design

“We are working with our collaborators at UW, the NIH, and the Bill & Melinda Gates Foundation to help create a safe and effective vaccine for not only SARS-CoV-2 but other coronaviruses as well,” said Neil King, who leads the IPD’s vaccine design efforts.

“This outbreak has illustrated that it’s all hands on deck, and all of us together against the bugs, in the fight against infectious disease. The good news is that the community has developed robust methods for antigen design and display over the last several years that are allowing the rapid generation of vaccine candidates that will likely be highly immunogenic.”