Focus Feature on SARS-CoV-2: Continuing the COVID fight
New mechanism; new pathway
Insights into coronavirus mutation may inform therapeutic research
By Jeffrey Bouley
SANTA CLARA, Calif.—A pair of antibody discovery companies— Antibody Solutions and Single Cell Technology (SCT)—is sharing research into the rise and dominance of a mutant SARS-CoV-2 virus that identifies a new mechanism which might indicate a competitive advantage for the mutation.
The predictions coming out of this research, if they hold up, could have a serious impact on the direction of future work on vaccines and therapeutics to deal with infection with the SARS-CoV-2 virus and COVID-19, the disease such infection brings about. The researchers hope that their findings could help biopharma scientists more effectively target their research efforts on specific regions of the SARS-CoV-2 virus that may contribute to its infectivity power and speed the discovery of an effective vaccine or therapy.
The researchers predict that the mutation they were studying may very well induce a structural change in the spike protein of the virus that would enhance virus entry. The study by the two companies is available on Preprints.org at https://www.preprints.org/manuscript/202005.0407/v1 but had not yet been peer-reviewed when this issue of DDN went to press.
According to Dr. John Kenney, president and co-founder of Antibody Solutions, the advanced molecular modeling used in the research for the study may have revealed how D614G, the dominant mutation isolated from a majority of patients in Europe and the eastern United States, gained a competitive advantage over the earlier isolates of SARS-CoV-2 found in China.
“Our results from gene sequencing clearly show the D614G mutation is more common as the pandemic unfolds,” Kenney said. “Our homology modeling identifies a mechanism whereby the D614G mutation favors the orientation of critical residues in the furin cleavage domain. You can think of the recently discovered furin domain as an activation sequence or ‘trigger.’ A better orientation of this domain for cleavage would be expected to enhance infectivity.”
In work on treatments to intervene in COVID-19, one of the primary targets has been the spike protein of the novel coronavirus. As Kenney and colleagues note, cleavage of the spike protein by furin is a key mechanism distinguishing SARS-CoV-2 from SARS-CoV and non-pathogenic coronaviruses.
“Our findings of the competitive and mechanistic advantages arising from the D614G mutation strengthen the rationale for targeting the furin cleavage domain of the spike protein with vaccines or neutralizing antibodies to inhibit COVID-19 progression,” Kenney said.
Dr. Chun-nan Chen, chief science officer and CEO of SCT, used his company’s informatics platform to mine worldwide SARS-CoV-2 genome data to learn more about how the mutants’ efficiency and geography may be correlated. Through genetic sequencing analysis of 11,542 viral genome records collected through April 28, 2020, Chen said his team was able to compute the frequency of different mutations.
“By examining amino acid changes in each case, we identified mutations along the Spike, or ‘S,’ protein at 103 positions,” Chen said, “And D614G was, put simply, the dominant mutation, occurring in 56 percent of all sequences—far more than all of the other identified mutations combined.
“When we examined the geographical distribution of G614-containing viral genomes,” he continued, “distribution patterns emerged that show the G614 mutant as the dominant SARS-CoV-2 mutant in Europe and large swathes of the U.S. But viral sequences from Chinese and South Korean patients and those from the West Coast of the U.S. were mainly found to be carrying the Wuhan Spike or ‘S’ protein genotype.”
The team modeled a three-dimensional protein domain of SARS-CoV-2 Spike protein with the goal of creating a prediction of the secondary structure of the region that contains both the site of mutation and the furin cleavage site that is believed to impart enhanced infectivity onto the virus.
“We created two models and observed a provocative result in which the only significant changes in structure are seen at the furin binding site,” Kenney explained. “Essentially, the D614G mutation changes the orientation of critical residues in the furin cleavage domain and is more favorably aligned within the active site of furin. If furin cleavage is rate-determining in the membrane fusion process, such an increase in protein cleavage would lead to more rapid membrane fusion and entry into cells that serve as hosts for the virus.
“So, our modeling predicts a conformational change in a specific cleavage site induced by the D614G mutation that may reduce the required activation energy and translate into an advantage in infectivity.”
Kenney, Chen and the other members of the team emphasize that understanding of whether this advantage is conferred by infectivity, immune evasion or pathogenicity—or some combination of these—is incomplete right now. And they caution that their research is not intended to draw specific conclusions about the D614G mutation’s transmissibility, sequelae influence or other broad immunological dynamics relating to the SARS-CoV-2 pandemic.
As Kenney noted, even if their findings hold up, they would not preclude other mechanisms that could act in concert with the one they have identified. To that end, the team is continuing to push toward a fuller understanding of the biology of the virus and why the D614G mutation seems to be so central to greater infectivity.
“This is a case where sequencing and molecular modeling working hand-in-hand can help build a greater understanding about the key mechanisms in the pathogenesis of SARS-CoV-2,” Kenney said. “Most mutations either fade from view or, if they stick, don’t have deleterious effects. We believe that the D614G mutation represents one of those instances where there’s a clear case of it increasing the pathogenesis of this virus, which points to the site we identified as an important target for therapeutic antibodies, vaccines and other modalities.”
“We hope this research provides an ideal engagement point for researchers working on SARS-CoV-2,” he continued. “This wasn’t an ‘obvious find,’ and it took both of our teams working closely together to reveal it. It was a unique insight that we hope will inspire the scientific community to continue exploring. Genuinely, we want to know what we have right and wrong, and we intend to explore therapeutic angles ourselves.”
Kenney said that in addition to its most recent collaboration with SCT, the company is working on multiple SARS-CoV-2 research initiatives on its own and on behalf of clients pursuing vaccines and therapies for the virus.
Commentary: Is a global approach for universal COVID-19 vaccine access achievable?
By Jamie Foster of Hill Dickinson
Every day brings news of another pharma or biotech company joining the race to develop COVID-19 vaccines and treatments. According to some reports over two hundred vaccines are currently in development.
At the outset of the crisis there was an emerging consensus that a global response would be needed, including for vaccine development. However, as the crisis has played out, this position seems to have changed as it has become clear that each country’s experience of COVID-19 and its response to the virus has been different. Demographics, hospital and diagnostics infrastructure and manufacturing capability for PPE have all played a part to date. And going forward, each country and its pharmaceutical industry is likely to have a different approach to vaccine development.
No one doubts the need for collaboration, particularly given the scale of what everyone is trying to deliver, both in terms of research and subsequent manufacturing and distribution. And there are hopeful signs of multiple significant collaborations having been established, including GSK and Sanofi, Astra Zeneca and the University of Oxford, Pfizer and BioNTech and Merck and Thermis. But the sector is used to collaborating, less so sharing the outputs of collaborations for universal access.
So is it really possible to harness the collaborative momentum generated by the global crisis to create an approach to vaccine development that will deliver equitable access on a global scale? Or will the realities of international drug discovery and development approaches prevent this?
Global initiatives to encourage collaboration
Building on existing World Health Organization (WHO) and United Nations initiatives, the WHO launched the COVID-19 Technology Access Pool (C-TAP) at the end of May with the aim of accelerating discovery of vaccines as well as other treatments.
A key element of the initiative is transparency, including in relation to disclosure of gene sequences and data, and results of clinical trials. Linked to this two elements are of particular interest from a legal perspective:
- Governments and other funders are encouraged to include clauses in funding agreements with pharmaceutical companies and other innovators about equitable distribution, affordability and the publication of trial data
- Potential vaccines, treatments and technologies developed in response to COVID-19 should be licensed on non-exclusive and global bases to the UN’s Medicines Patent Pool, and/or made available through other public health research and development mechanisms, consortia or initiatives that facilitate global and transparent access, and/or voluntary non-enforcement of intellectual property rights.
Predictably enough, there is skepticism about whether a voluntary initiative of this nature can succeed. One might say that it is easy enough for the pharma giants to support the initiative in principle without ever giving access to their intellectual property (IP) in the manner envisaged.
Exploiting IP generated by collaboration
Of course, the argument runs that any attempt to pool IP stifles the incentive to innovate. And the potential of any pharma or biotech company to develop drugs and technologies lies largely with its portfolio of IP and its capacity to protect it. The research-intensive nature of these companies means that their most important assets are the results of their research, which is both expensive and time consuming to undertake. But when companies are being funded directly by government to develop vaccines, and so using less of their own revenues, should they be giving more of their IP away for free or at discounted prices?
In the United Kingdom, one of the high-profile vaccine projects which has had government funding allocated to it by the UK’s Vaccines Taskforce is the collaboration between Astra Zeneca and the University of Oxford, with Astra Zeneca already having secured contracts with the U.K. and U.S. governments for delivery of the vaccines if successful.
One could argue that in this case the patents arising from the collaboration should not be treated as a private asset for exploitation but rather as a public asset to be licensed freely. But that may not be feasible, particularly given the number of vaccines under development and the consequential disincentive to continue funding research if similar work is already being advanced by other collaboratives (independently) or that competing IP is available or at a more advanced stage of development.
Perhaps the focus instead should be on finding mechanisms to allow Astra Zeneca and others in their position to retain ownership of their IP and benefit from a return on investment, while also allowing equitable distribution of their products. That may result in lower drug prices than ordinarily expected, but that may be an acceptable compromise.
Protecting IP used to develop vaccines
The IP we are talking about in response to the COVID-19 crisis is not limited to patents generated from vaccines. There is also the IP arising from drug discovery processes. And there is no hotter IP in that space than IP arising from artificial intelligence (AI)-driven processes.
It is well understood that the intersection of AI and intellectual property presents complex legal and ethical issues, for example whether autonomously AI-generated inventions should be patentable, and whether AI systems should be capable of ownership through intellectual property rights. There is also the issue of disclosure of AI algorithms from both a legal perspective (for patenting purposes) and ethically (for example, the U.K. government’s Code of conduct for data-driven health and care technology [July 2019] is explicit that the functionality and learning methodology of algorithms should be clear and transparent).
This is a live conversation—many of these issues were raised in the WIPO Conversation on Intellectual Property and Artificial Intelligence draft issues paper (December 2019). But the search for COVID-19 vaccines brings them to the forefront of considerations.
It seems highly unlikely that pharma companies and their collaborators will be prepared to grant licenses to competitors in relation to any innovative technologies they already have or develop for the purpose of vaccines. Again, this may slow down or inhibit the development (and speed of development) of vaccines which can be distributed for universal access.
None of the issues raised above are intended to cast doubt on the ambition of a universal access approach, or the willingness of companies to signal their participation in related initiatives, but a recognition of the reality of the way in which the sector collaborates and operates is needed to manage expectations and, perhaps, maximizes the chances of success.
Jamie Foster is a partner in the Life Sciences division of Hill Dickinson LLP. (More information at www.hilldickinson.com/people/jamie-foster)
Looking at the frontrunners
Three compounds are in the spotlight now as new and repurposed drug options are examined for COVID-19
The research into vaccines or therapeutics for SARS-CoV-2 infection and full-fledged COVID-19 disease continues to be fast and furious, both in terms of trying to find novel treatments for various pathways and also finding existing drugs that might have an impact.
And in spite of—or perhaps because of—the pushback against using the antimalarial drugs hydroxychloroquine and chloroquine for COVID-19, the enthusiasm for some of these potential therapeutics is high. At the same time, many are remembering the lesson of those malaria drugs as questions arose about efficacy and concerns spiked around potential adverse health effects on COVID-19 patients.
In the arena of therapeutics for the disease, three names are generating a lot of interest right now: remdesivir, dexamethasone and fluvoxamine.
Data and analytics company GlobalData anticipates that Gilead’s remdesivir will target a select severity group of COVID-19 patients, noting that it remains questionable as to how treatment with the drug will be initiated and optimized.
“Gilead’s remdesivir was trialled in a number of patients with varying severities, however, it was noted that the drug did not provide benefit to mild or critically ill COVID-19 patients who required ventilation or extracorporeal membrane oxygenation. Hospitals are therefore limited to targeting a select population of moderate to severe patients,” explained Angad Lotay, an infectious diseases analyst at GlobalData.
“Furthermore, the latest evidence did not provide guidance on how to optimize treatment or whether earlier initiation with remdesivir reduces mortality rates. With additional data from Gilead’s SIMPLE trial expected, patients with the highest unmet medical needs are still left without an optimal treatment option.”
Remdesivir has a broad spectrum antiviral activity and acts as a viral RNA polymerase inhibitor. However, it exerts minimal cytokine responses necessary to manage patients who are critically ill and require ventilatory support. In a bid to target this population, Gilead has been testing remdesivir with immune modulators to tackle the enormous immune reactions that strike patients in the latter stages of this disease.
Dexamethasone, for its part, was shown to save the lives of seriously ill patients with COVID-19. Dexamethasone is a corticosteroid used in a wide range of conditions for its anti-inflammatory and immunosuppressant effects.
As the World Health Organization (WHO) noted recently, “It was tested in hospitalized patients with COVID-19 in the United Kingdom’s national clinical trial RECOVERY and was found to have benefits for critically ill patients.”
According to preliminary findings shared with WHO, the treatment was shown to reduce mortality by about one-third for patients on ventilators; for patients requiring only oxygen, mortality was cut by about one-fifth.
Although June was when much of the buzz about dexamethasone emerged, AI VIVO—a company combining systems pharmacology and artificial intelligence (AI) to accelerate drug discovery—reported that its platform correctly identified dexamethasone as having high potential for the treatment of COVID-19 in April 2020. While the company touted this as demonstrating the ability of AI VIVO’s platform to systematically and correctly identify candidates with the highest chance of therapeutic success, it also points to the importance of efforts overall to mine existing drugs for potential COVID-19 therapeutics.
“After receiving a world-first approval by the U.K. government, following groundbreaking data showing it can reduce COVID-19 deaths among hospitalized patients, the inexpensive and widely available corticosteroid dexamethasone has been getting significant attention,” noted Dr. Arafa Salam, an infectious diseases analyst at GlobalData. “While data supporting dexamethasone’s efficacy seem clear, the magnitude of its benefit remains modest. Further, additional studies are warranted so as to avoid the same roadblocks as hydroxychloroquine, where significant variations in results muddied the ability to determine its role in COVID-19 treatment.”
Although the data do identify an improvement in mortality with dexamethasone, its place in COVID-19 treatment modalities remains unclear, according to Salam, who pointed out that one of dexamethasone’s key competitors, remdesivir, saw clinical improvement in 36 of 53 patients (68 percent); however, with dexamethasone mortality was reduced by 17 percent—and while reductions in mortality with remdesivir trended downwards, the differences were not statistically significant.
“Something to consider is the combination of these two drugs, as they have differing mechanisms of actions, which could be complimentary, with remdesivir slowing damage due to the virus and dexamethasone slowing damage to a hyper-inflammatory state,” Salam continued. “This type of scheme is already being considered in trials with remdesivir and the anti-inflammatory IL-6 inhibitor tociluzimab, so the thought of the combination of remdesivir and dexamethasone isn’t too farfetched.”
Of the three compounds we’re looking at in this roundup, perhaps the most surprising is fluvoxamine, because it is used primarily to treat depression. But researchers frame the drug as a potential treatment for the “cytokine storm” associated with COVID-19. If found effective, this selective serotonin reuptake inhibitor (SSRI) could be rapidly made available to patients as it is already globally marketed and has a known safety record, says GlobalData.
“Having a treatment for cytokine storm that is already so easily available will help reduce mortality and prevent progression from mild-to-severe COVID-19,” noted Johanna Swanson, a product manager at GlobalData.
Fluvoxamine is being investigated for COVID-19 treatment based on results from researchers at the University of Virginia School of Medicine, who found that the drug could prevent sepsis and reduced the generation of cytokines in mice.
“While it remains to be seen if fluvoxamine will have the same effect in humans as it does in mice for preventing sepsis, this would also indicate that the drug could be repurposed for treating other cytokine storm diseases in addition to COVID-19,” Swanson said.
As noted by Washington University, “Fluvoxamine, which is in the class of drugs called selective serotonin-reuptake inhibitors, also interacts with a protein important to the body’s inflammatory response. This effect may help relieve an overwhelming immune response, which is thought to occur in about one in seven COVID-19 patients, who then often end up hospitalized, and sometimes on ventilators, with a higher risk of death.”
Illumina commits $10M to COVID-19 response and research
SAN DIEGO—Illumina Inc. announced that as researchers and others unite to combat COVID-19 that “giving back is in our DNA, and together with the Illumina Corporate Foundation, we have committed more than $10 million to support the communities where we live and work. As we champion the greater good, Illumina is focused on making sequencing accessible around the world to fight the pandemic together through the power of genomics, collaboration and global care for each other.”
To support public health efforts associated with SARS-CoV-2 surveillance, sequencing and monitoring, Illumina is providing in-kind donations valued at approximately $5 million dollars for instruments and consumables. In addition, it has dedicated more than $2 million to COVID-19-related research efforts.
Also, to advance scientific research, Illumina recently released the SARS-CoV-2 Data Toolkit, making it easier for researchers to detect and identify the viral sequence in their samples and contribute their findings to critical public databases. The toolkit is freely accessible on BaseSpace Sequence Hub until October 2020.
“We will do everything we can to deliver next-generation sequencing technology to power the scientists, researchers and clinicians on the frontlines of the fight against COVID-19,” said Francis deSouza, CEO of Illumina. “And, we will not stop there. In addition to our technology, we are dedicated to making a positive impact on humanity through our actions to empower our communities.”
The Illumina Foundation has awarded more than $3 million in philanthropic donations, of which $1 million has gone to the CDC Foundation COVID Emergency Response Fund and $2 million to local community-based initiatives in the areas where Illumina operates.
Ayurveda phytoactive ingredients vs. coronavirus disease
FRANKFURT, Germany & HAARLEM, Netherlands—FIZ (Frankfurt Biotechnology Innovation Center GmbH) and Sri Sri Tattva Europe B.V. are collaborating to possibly fight against COVID-19 through Ayurveda.
A new research collaboration network initiated and led by FIZ will analyze within the “Ayurgenomics” project whether Ayurveda phytoactive substances can support the human body against the coronavirus SARS-CoV-2. FIZ network partners are examining the potential anti-inflammatory and immune-boosting properties of an Ayurveda product known as “Shakti drops.” The Ayurgenomics project overall aims to develop evidence-based guidelines to integrate Ayurveda principles and practices in modern medicine.
“We are very pleased to take initiative in this extraordinary research project and thus also to be able to make our contribution in the fight against the coronavirus,” explained Dr. Christian Garbe, managing director of FIZ.
The research team will focus on two indication areas: firstly, inhibition of viral entry and secondly immune-boosting effects.
Nanomaterial enhances potential COVID-19 therapeutic
WEST LAFAYETTE, Ind.—Niclosamide, a drug used to treat tapeworms, has shown potential to have strong antiviral effect against SARS-CoV-2, but the drug itself has limited potential because its structure makes it difficult to dissolve and for patients to absorb.
Purdue University scientist Yuan Yao’s laboratory has developed a potential solution: a plant-based, highly potent nanoparticle called OHPP (octenylsuccinate hydroxypropyl phytoglycogen) that can solubilize and enable niclosamide. Niclosamide’s solubility reportedly can be increased more than 5,000 times with OHPP, and the drug is effectively released to cells.
“Niclosamide has a tough, crystalline structure. When given to the human body, it may behave like sand, not effectively releasing the compound to provide therapeutic effects,” said Yao, an associate professor in the Department of Food Science at Purdue. “But using OHPP, we can solubilize these crystals, potentially making niclosamide bioavailable as a drug for COVID-19.”
Affimer reagents may block coronavirus interaction with ACE2
CAMBRIDGE & WETHERBY, U.K.—Avacta Group plc., the developer of Affimer biotherapeutics and reagents, recently announced that several of the Affimer reagents recently generated for development of a point-of-care COVID-19 antigen saliva test have now also been shown to block the interaction between the virus’ spike protein and ACE2, a receptor on human cells that is key to the virus infection pathway.
Avacta has already successfully generated a large number of Affimer reagents that bind to the SARS-COV-2 virus’ spike protein as part of its partnership with Cytiva (formerly GE Healthcare Life Sciences and now part of Danaher Corp). As previously announced, Avacta and Cytiva are working together to develop a rapid point-of-care COVID-19 antigen saliva test to be mass produced for large-scale population screening and for self-testing by consumers.
Further work at Avacta has now shown that several of these Affimer reagents block the interaction between the virus’ spike protein and a receptor found on human cells, called ACE2, to which the virus spike protein binds in order to infect cells. Affimer reagents that block the binding of the virus spike protein to ACE2 therefore have the potential to prevent infection and act as “neutralizing” therapies.
Neutralizing therapies could be given to those exposed to the virus (such as health and social-care workers) to prevent infection, as well as to patients already infected by the virus, to help treat and prevent disease progression.
“This is a very exciting development in the COVID-19 program,” said Dr. Alastair Smith, CEO of Avacta Group. “It only took four weeks to generate more than 50 Affimer reagents that bind the SARS-COV-2 virus spike protein and amongst those we now know that there are neutralizing Affimers that block the interaction with a key human cell surface receptor, raising the potential for a therapy to prevent infection.”
Recently GSK invested $250 million in Vir Biotechnology Inc. to develop potential antibody treatments for COVID-19 by selecting antibodies from recovered patients, and AstraZeneca also recently announced that it would start a program to find new monoclonal antibodies that block the spike/ACE2 interaction, he pointed out.