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Research Program on COVID-19/SARS-COV-2

Below is a description of the approaches that provide the best opportunities to prevent and treat COVID-19/SARS-COV-2. Having a vaccine that is safe and effective and available at population scale would be ideal; most estimates are that it will be >1 year to have an effective vaccine deliverable at scale, and there are well-founded cautions that vaccine development may be less straightforward than hoped. Consequently, parallel approaches are needed to provide alternative means of prevention and therapy. Projects undertaken by Rockefeller Heads of Laboratory and their teams address key needs
in the field. These include:

(a). Near-term efforts to get repurposed therapeutics and/or convalescent plasma into use that will have some efficacy that can reduce the incidence of advanced disease in vulnerable patients and prevent infection in front-line health care workers.

(b). Longer-term development of innovative antibody and other protein therapeutics to inhibit viral infection of cells (passive immunity). These can play important roles if vaccine development is delayed or work in addition to vaccines in people who cannot respond to (many in the elderly population) or have not obtained vaccine.

(c). Longer-term development of novel small molecules targeting known and novel targets identified from cell-based and human-based genome-scale and biochemical studies that are more specific and more potent than current options that can stop viral infection.

(d). Development of new tools to enable 1. High-throughput screening for novel chemical leads (<3 months); 2. Rapid assays to identify patients who have recovered from SARS-COV-2 infection and have high titers of broadly neutralizing antibodies (<3 months). 3. Blood drop assays to identify people who have recovered from infection and have SARS-COV-2 antibodies that protect them from recurrent infection; these people would be candidates to work in environments in which repeated exposure is likely, and would identify people and populations at risk. Broad application of these tests would provide insight into level of past exposure in a community, important for assessing future risk and need for vaccine.

(e). Sensitive rapid-turnaround diagnostic tests of early infection to enable early intervention with effective therapy.

These projects we are working on are from an incredible group of scientists who have made seminal contributions to science and medicine, including the cure for hepatitis C, prevention and treatment of HIV, modification of antibodies to optimize their biologic activities, identification of host factors that contribute to disease susceptibility, as well as fundamental contributions to the basic science of viruses and the immune system.

The projects currently underway are as follows:

CONVALESCENT PLASMA FOR NEAR-TERM PROPHYLAXIS AND TREATMENT. Many patients with Sars- CoV-2 infection recover without complications. This is because their immune systems have produced antibodies that neutralize the virus, meaning they prevent the virus from infecting our cells. The same antibodies that allowed these people to recover can be transferred to other people to prevent or treat infection. They would be ideally used in front-line health care workers to prevent their infection from decimating the workforce. A single dose of plasma can typically be effective for more than a month. These antibodies can also be used early in the course of infection to prevent people at high risk of serious infection- such as the elderly and people with serious underlying health problems- from progressing. This use of ‘convalescent plasma’ has been used in different forms for over 100 years.

The method of doing this is simple. Blood from recovered patients is fractionated to remove all the cellular material – red blood cells, white blood cells and platelets – and collect the remaining plasma. This plasma is studied to determine how well it neutralizes the virus, is treated to kill or inactivate all potentially infectious agents, and then administered. Members of the Rockefeller community are joining forces with collaborators at Columbia University and the New York Blood Center to pilot this effort and then hope to scale up as a sizable cohort of recovered patients develops. With thousands of
New Yorkers infected, within weeks we expect there to be enormous opportunity to recruit sufficient samples to protect the healthcare workforce and treat patients in need. Blood sampling can be done at the NY Blood Center nearby the campus, or at outlying sites. Efforts to simplify collection to increase the scalability of the approach are being explored. This plasma collection protocol is complementary to the next project below. These plasma samples can potentially be in the clinic in the near term.

DEVELOPMENT OF HIGHLY POTENT MONOCLONAL ANTIBODIES FOR PROPHYLAXIS AND TREATMENT. It will be desirable to identify several highly potent antibodies that when given in combination can prevent or stop viral infection. Several years ago, immunologist Michel Nussenzweig developed a robust method for purifying the ‘B cells’ that are making specific antibodies of interest in people, cloning the genes that produce these antibodies, allowing the production of these antibodies in large quantities for clinical use. He has effectively used this method to develop an antibody-based treatment for prevention and control of established HIV infection. He will now repeat this trick for COVID-19. This project will be collaborative with Rockefeller virologists Paul Bieniasz and Theodora Hatziioannou, as well as with the Rockefeller University Hospital. Paul and Theodora are developing a greatly simplified and rapid method to assess the level of neutralizing antibodies in each recovered patient’s blood that does not require the use of live COVID-19. The assay they are developing will be vital to both of the first two projects described. Because these antibodies are identified in patients who successfully recovered from infection, they are highly likely to be clinically effective and could be
in the clinic in a year.

OPTIMIZATION OF ANTIBODIES. Antibodies are made of a highly variable ‘front end’ by which they bind very specific targets, and a ‘back end’ Fc portion that binds to specific immune cells via receptors that are specific for Fc. Immunologist Jeffrey Ravetch discovered that modifying the Fc portion of antibodies can drastically change the effects antibodies have when they bind immune cells. He will study antibodies made by people who have been infected with SARS-CoV-2 to determine which Fc variants are best capable of eliminating virus, and ensuring that Fc’s that can inhibit viral neutralization do not move into the clinic. His group has also produced mice with humanized Fc receptors that can be used in conjunction with humanized ACE2 (the receptor by which SARS-CoV-2 enters cells) to produce an infectious model that can test in vivo the effect of different Fc modifications on the immune response.

DEVELOPMENT OF DECOY RECEPTORS. The SARS-CoV-2 virus enters cells by its ‘S’ protein attaching to the cell surface protein ACE2. Paul Bieniasz and Theodora Hatziioannou are fusing the key parts of the ACE2 receptor to the Fc region of antibody molecules. These molecules can bind to the S protein on virus particles and neutralize them and also target virus-infected cells for destruction by Fc binding to immune cells. This approach has the potential to prevent or treat not just infection by SARS-CoV-2 but by the many other coronaviruses in humans and bats that use ACE2 as their receptor for cellular invasion. Thus, this agent may be critical not just for this epidemic but may be able to quickly snuff out future coronavirus epidemics. This is particularly important given that three coronaviruses (SARS, Mers and now SARS-CoV-2) have jumped from animals to humans with serious consequences in recent years. These decoy receptors can potentially be in animal testing in a few months.

NANOBODIES FOR PREVENTION AND TREATMENT OF COVID-19. Nanobodies are a novel class of very small antibody-like molecules found in the blood of camels and related species. Because of their small size and simplicity, they can be manufactured at low cost, have high stability, low immunogenicity, and can be of very high affinity, making them excellent candidates for therapeutics and diagnostics. Because of their high stability, they can be a rapid point-of-care diagnostic and can potentially be used for inhaled delivery to the lungs

Structural biologist Michael Rout and chemist Brian Chait will select high affinity and potently neutralizing nanobodies that bind to different, non-overlapping, epitopes on the target – initially, the SARS-CoV-2 Spike Glycoprotein that is used to enter cells – and then format these nanobodies as higher level multimers to improve affinity and test whether these have greater neutralizing ability. They will be further engineered to improve their efficacy and required properties.

RAPID SCREENING TESTS FOR SARS-COV-2. A major clinical issue has been the failure to deploy rapid, reliable and highly scalable methods to diagnose SARS-CoV-2 infection. Physician-scientist Bob Darnell is working on new methods to rapidly diagnose infection and develop a model by which patients could potentially do simple at-home sample collection that can be sent in for testing. The rapid testing can be up and running in weeks, which will also be important for quickly identifying members of our local workforce who have acquired infection, preventing spread of infection among essential employees on campus. This effort will be able to integrate with and enable the studies of JL Casanova (see below), using analysis of at-risk individuals from NYC.

IDENTIFYING THOSE NO LONGER AT RISK OF COVID-19. Biochemist Tom Tuschl is seeking to develop a rapid and sensitive blood-drop antibody test to determine who in the population has been exposed to SARS-CoV-2 and has a significant antibody titer to the virus. This will be important for assessing and following the health of the population. This may also be of critical importance in reassuring people who are no longer at risk of becoming infected or spreading the disease, which may become crucial for sustaining the workforce in health care facilities, among first responders, and other vital occupations.

UNDERSTANDING THE COURSE OF SARS-COV-2 INFECTION. One of the puzzles of this virus is the unknown incubation period of the virus, with the classic story being development of escalating symptoms 4-7 days after exposure, but some patients having potentially long incubation periods during which they may be infectious and expose many people. In the latter case, waiting until classic symptoms appear will not help prevent wider spread of the virus. It’s also not known how long the virus persists after symptoms subside. Biochemist and physician Tom Sakmar is developing the coronavirus calendar, CoronaCal, which starts with healthy people in the community who report symptoms and provide a saliva sample every day for up to 90 days. At the end of the evaluation period, the saliva samples can be assayed for presence of viral RNA. These studies will provide critical information about how the infection begins and propagates through the population. Tom is also working with Rockefeller Research Hospital pharmacist Robert MacArthur on a clinical pharmacology guide for current drugs that might be effective for COVID-19 prevention or treatment.

NEW MEDICINES FOR COVID-19 AND ITS SUCCESSORS: INVESTING FOR THE NEAR TERM AND LONGRUN. SARS-CoV-2 is increasingly likely to become endemic in the population, lasting many years. There is consequently a pressing need for much better medicines to treat COVID-19. The most promising agent in the clinic at present, called Remdesivir, inhibits the virus’s RNA polymerase, a key enzyme required for viral replication and pathogenicity. Remdesivir was developed in large part for use against a very different virus, Ebola, and is far from optimized for COVID-19. There is clearly need for more medicines.

REPURPOSING DRUGS. In the near term, virologist Charlie Rice, who won the Lasker Award for developing the methods that enabled high throughput screens that led to the cure for hepatitis C, is developing related high-throughput assays to screen for new inhibitors of SARS-CoV-2 replication and also developing coronavirus replicon systems with convenient reporters that can be used for testing novel molecules for their ability to inhibit SARS-CoV-2 replication. He is collaborating with Fraser Glickman, who directs the Rockefeller High Throughput and Spectroscopy resource center, who has assembled a large collection of registered drugs from around the world and others that have been safe in humans but have not been registered for any therapy. Success with any of these would have a rapid route to FDA approval and clinical use.

NEW TARGETS FOR THERAPY. Charlie Rice is coupling this effort with doing highly innovative work using CRISPR technology to knock out genes in the human genome to screen for those whose loss prevents infection by SARS-CoV-2. He has already identified a gene called LYE6E as a gene that’s essential for entry of the virus into cells. Charlie’s lab will also do screens that combine CRISPR with drug candidates to identify genes that might be targeted to increase the efficacy of known or candidate drugs.

A parallel approach to this is being taken by Jean-Laurent Casanova, a superb human geneticist who has identified many genes whose mutation causes unusual susceptibility to infectious agents such as the bacterium that causes tuberculosis or the influenza virus. He is now collecting DNA samples from patients from around the world who have had unexpectedly severe courses of COVID-19 or who have had many exposures but have unexpectedly remained free of disease. This approach has the potential to identify host targets that mediate susceptibility or infection in not just the cells that become infected, but also in cells of the immune system that fight infection.

IDENTIFICATION OF NEW LEADS FOR THERAPEUTICS RNA-DEPENDENT RNA POLYMERASE. In the longer term, two heads of laboratory have innovative approaches to developing new inhibitors of the viral RNA-dependent RNA polymerase, likely the key target for inhibiting viral replication. Chemist Sean Brady has pioneered the discovery of novel antibiotics made by bacteria in soil, using novel methods that do not require the isolation and culture of these bacteria. He has extended this work to the human microbiome, where he has shown that there are many novel nucleosides that are likely involved in inhibition of RNA and DNA polymerases made by different bacteria and viruses. These provide a large untapped source for identifying new leads for a potent and specific inhibitor of the SARS-CoV-2 RNA polymerase that can be tested in screening assays being developed by Charlie Rice.

HELICASE. It is important to have drugs that work on targets beyond the RNA polymerase. SARS-CoV- 2 has an essential helicase that is required for unwinding double-stranded RNA templates during viral replication. It is likely that inhibitors of this enzyme can be found that are specific for the virus without effects on human proteins. Tarun Kapoor is an exceptional chemical biologist with extensive experience on this class of molecule. Charlie Rice has also worked on the Hepatitis C helicase. And there is published work on inhibitors of the related MERS virus helicase that can be used as a starting point. They will collaborate to identify novel compounds that inhibit the SARS-CoV-2 helicase that can be taken into the clinic.

Promising inhibitors of the virus can be followed up rapidly in collaboration with our medicinal chemistry capability at the Tri-I Therapeutics Discovery Institute led by Pete Meinke to optimize small molecules to go into pre-clinical animal testing with the hope of developing drug candidates.

NEW ANIMAL MODELS FOR TESTING. Animal models to support pre-clinical testing of inhibitors of SARS-CoV-2 are not very good and not generally available. The SARS-CoV-2 virus enters cells by its ‘S’ protein attaching to the cell surface protein ACE2. Immunologist Gabriel Victora will use his expertise in application of CRISPR technology to make the mouse ACE2 receptor identical to its human counterpart, with its expression properly controlled. This has the potential to be an ideal model enabling the next step in advancing drug candidates toward clinical testing. Gabriel will also characterize how antibodies that prevent SARS-CoV-2 infection act, focusing on mapping where in the S protein they bind, potentially identifying antibodies that are each effective but act at different sites on the molecule that might be potent combinations for therapy and prevention. These can be used in conjunction with Jeff Ravetch’s humanized Fc receptor mice, enabling an excellent model of human infection in the pre-clinical setting.

BASIC SCIENCE TO DESIGN BETTER DRUGS. Structural biologists Seth Darst and Elizabeth Campbell are experts in determining the structure of RNA polymerase complexes bound to the templates that they copy. The SARS-CoV-2 RNA polymerase is essential for viral replication and a prime target for drug treatment. By understanding in atomic-level detail how existing inhibitors bind and inhibit the enzyme, they can identify ways to modify current inhibitors to make them specifically effective against SARSCoV- 2. In collaboration with biochemist Brian Chait, they will also identify all the proteins comprising the RNA replication complex in living cells. This will likely include proteins made both by the virus and by host cells, which may identify new therapeutic targets. They plan to determine the atomic-level structure of the complex by cryo-electron microscopy.

Immunologist Sasha Tarakhovsky is studying the role of SARS-CoV-2 Nucleocapsid Phosphoprotein (NP) on virus-induced cell death in infected cells. He has identified the likely viral protein responsible for this effect and is working to understand the mechanism, with a goal of finding ways to prevent its occurrence. His work suggests that inhibitors that target proteins of the BET family may be useful targets, and these will be tested in collaboration with Charlie Rice.