Information
Here is a fabulous real-time resource from Johns Hopkins for tracking all things related to SARS-CoV-2 cases etc. around the world.
Screenshot of the Johns Hopkins Coronavirus Resource Center webpage.
On Thursday, March 19th, Bill Gates published on his website Gates Notes a super helpful Question & Answer session that he had on Reddit on the SARS-CoV-2 pandemic. He answered 31 questions that people had for him. Here are some of the highlights that we took to heart after reading his post.
Wash your hands with soap often & don’t touch your face!
Respect social distancing (i.e., the “shut-down”) — it will help and is the best thing we have to help prevent overwhelming our hospitals beyond their capacity. (However, because of the epic failure of the U.S. SARS-CoV-2 testing system, hospitals are preparing now for going beyond their surge capacity that will start occuring in the first two weeks in April. This is going to be a terribly difficult time.)
The lack of SARS-CoV-2 testing and organization of testing in the U.S. has made the negative impacts on our society and economy much worse than it needed to be. If we did this amazingly well early-on (like South Korea or back in Dec 2019 when the outbreak was first identified in Wuhan, China), we would be nowhere close to the awful depths of where we’re currently at. This is a huge failure of our government and leaders who are responsible for pandemic preparedness.
A safe & effective SARS-CoV-2 vaccine (which will take about 1 year from now before its possible to administer widely to people, if the research & development goes well) is one of the most powerful solutions to overcoming this pandemic and moving on as a civilization.
Take models and projections of timeframe and # of infections/cases with a grain of salt at this time — we just don’t have good data yet to parameterize these models well.
This hellish experience will whip us in shape and we’ll be much better prepared for the next pandemic that comes our way.
Currently, there are 6 potential SARS-CoV-2 vaccine platforms that are being manufactured and tested in animals and/or humans. They are:
mRNA
DNA
Subunit (components [i.e., antigens] of the virus)
Virus-like particles displaying subunits
Whole virus (inactivated) — meaning killed
Whole virus (attenuated) — meaning weakened
Below is a table listing advantages and disadvantages of some of these vaccine platforms that have been developed and are currently in testing for SARS-CoV and MERS-CoV from Prompetchara et al. 2020.
Moderna (“ModeRNA”) (a biotech company in Cambridge, Massachusetts) launched the first ever human clinical trial for a SARS-CoV-2 vaccine last week on Monday, March 16, 2020, at Kaiser Permanente Washington Health Research Institute in Seattle. The study is funded by the National Institute for Alergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). That’s an incredibly fast 2-month turnaround from the time that the SARS-CoV-2 genetic sequence was publicly disclosed on January 5, 2020, to having a manufactured vaccine ready for human testing. This rapid development of a potential vaccine is unprecedented.
The key to this rapid pace is that Moderna’s core technology — synthetic mRNA encapsulated into lipid particles — is readily manufacturable and scalable (much more so than growing and purifying individual proteins in huge bioreactors). These mRNA-lipid particles are injected into muscle tissue, and the cytoplasm in muscle cells then become little temporary factories that translate the mRNA into the encoded viral protein, which then triggers the immune system to generate responses against the viral protein so the immune system can recognize and attack actual viruses that have these same proteins when they infect an immunized person. (Two German biotechs called CureVac and BioNTech have developed similar technology and are a few of many companies competing with Moderna to develop a SARS-CoV-2 vaccine.)
A 2017 article in Science by Kelly Servick described Moderna’s core technologies for synthesizing the mRNA (or “hacking” the rules for mRNA) and making the lipid particles such that they efficiently encapsulate and deliver the mRNA to cells. The following is a summary of key takeaways from this article:
By leveraging the cell’s own ribosomes in the cell’s cytoplasm to make protein encoded by the foreign mRNA, this makes it possible to deliver proteins that act inside cells or span across their plasma membranes, which is difficult to do by delivering pre-made proteins from the outside.
A drawback of DNA gene therapy is that it can unpredictably integrate into the genome; this is not the case with mRNA.
RNA invading a cell from the outside is a hallmark of viruses — it’s how SARS-CoV-2 infects cells and reproduces! Our immune system has evolved sophisticated ways to recognize and destroy invading mRNA, but obviously from the devastation that SARS-CoV-2 is causing on the human race, our cells and immune systems haven’t figured everything out yet! Moderna has modified the chemical structure (or shape) of uridine to prevent it from locking into activating immune receptors (adenosine, cytidine, uridine, and guanosine are the 4 predominant nucleosides that makeup RNA). Katalin Kariko and Drew Weissman of University of Pennsylvania figured out in the 2000s that the cell’s inflammatory response to invading mRNA can be tamed by modifying the shape of uridine into pseudouridine, which is a natural variant found in the body. They reported in 2005 that pseudouridine greatly reduced the tendency of sentinel cells called dendritic cell from shooting out inflammatory molecules in response. Moderna figured out new uridine modifications that would dampen the anti-mRNA immune response even further than pseudouridine. They found 1-methylpseudouridine was the best at evading immune detection and was stable enough to make a therapeutic. (Kariko now leads a research team at BioNTech in Germany.)
Moderna has figured out how the folding of the mRNA impacts the efficiency of ribosomes to read the mRNA and make protein (from research by Melissa Moore at the University of Massachusetts Medical School in Worcester — she’s now CSO of Moderna’s research platform). Moore discovered that mRNA strands that have more nucleosides that tightly stick together and form tighter secondary structures are more readily translated into protein by ribosomes.
Moderna has attached non-coding mRNA sequences outside of the protein coding sequence that allow mRNA translation to occur only in the specific cell subtypes that are relevant for creating a vaccine response or treating a certain disease. In other words, translation of the delivered mRNA will not occur in cells/tissues that it doesn’t belong.
Moderna has engineered lipids to make them more biodegradable and safe when administered to the body. They are also working with nonlipid formulations — polymers — which are known to have low immunogenicity.
Messenger RNA (mRNA) is translated into a protein by a ribosome. V. ALTOUNIAN/SCIENCE
Schematic of Moderna’s core technology. V. ALTOUNIAN/SCIENCE
Moderna’s pipeline as of March 21, 2020.
Here is a nice paper that extensively reviews the different potential treatments that are being considered for COVID-19.
Here is a NYTimes article by Carl Zimmer that links to the above article and describes the efforts to discover a COVID-19 therapy.
“Hundreds of Scientists Scramble to Find a Coronavirus Treatment“
Chemical structure of hydroxychloroquine (approved for treatment of malaria infection and autoimmune diseases such as rheumatoid arthritis and lupus)
Hydroxychloroquine (HCQ) may be used to prevent and/or treat SARS-CoV-2 infection, but better designed and conducted studies are needed to see if this is in fact true. It, along with the investigational intravenous antiviral remdesivir, is currently among the most promising treatments for COVID-19 patients.
The NIH’s DailyMed website lists that HCQ is currently indicated to
prevent and treat malaria
treat lupus
treat rheumatoid arthritis
Below are some data from two recent studies that have suggested that:
chloroquine (which is similar to HCQ but has a worse safety profile than HCQ and lower in vitro activity against SARS-CoV-2) is effective at killing SARS-CoV-2 that have infected human cells that are grown in a petrie dish in the lab (Wang et al. 2020), and
hydroxychloroquine in combination with the antibiotic azithromycin is an effective treatment regimen for COVID-19 (Gautret et al. 2020), however, this study was done in very few patients and the control group was not randomized and clinical benefit was not properly assessed. It involves flawed and limited science (e.g., six HCQ-treated patients were excluded from the study: 3 of these went to the ICU, 1 died, 1 decided to stop treatment due to nausea, and 1 left the hospital and was PCR-negative for SARS-CoV-2). This study is not a good model of the human population and these data can only be treated as anecdotal evidence at this point. It’s important to note that hydroxychloroquine and azithromycin are associated with QT prolongation and caution is advised when considering these drugs in patients with chronic medical conditions (e.g., renal failure, hepatic disease) or who are receiving medications that might interact to cause arrythmias. PLEASE TALK TO YOUR PHYSICIAN BEFORE TAKING ANY OF THESE DRUGS — information in this blog post and anywhere else on our website is intended for EDUCATIONAL PURPOSES ONLY and DOES NOT CONSTITUTE MEDICAL ADVICE.
In vitro viral inhibition data from Wang et al. 2020.
Time course of % of patients with detectable SARS-CoV-2 mRNA on different treatment regimens (N=16 controls; N=14 HCQ only; N=6 HCQ + azithromycin) from Gautret et al. 2020.
Patient characteristics and time course of SARS-CoV-2 viral levels in patients from Gautret et al. 2020.
Table of time course of patient outcomes from Gautret et al. 2020.
A March 18 study published by Cao et al. in the New England Journal of Medicine showed that “In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care.“
Graph from Cao et al. 2020 showing that there is no statistically significant difference between patients treated with lopinavir/ritonavir and those not treated in the time course of how quickly they experience clinical improvement.
Graph from Cao et al. 2020 showing that there is no statistically significant different in the time course of viral load reduction between patients treated with lopinavir/ritonavir and those not treated.
We’re all spending a bunch of our time at home during this COVID-19 “shut-down”. Here are some great online educational resources to pass time and share with your loved ones and friends:
Enjoy and happy learning!
One of the many cool things happening at the Institute for Protein Design (IPD) where Jake works is that anyone out in the world can play the computer game Foldit to design proteins from scratch. It’s a great way for kids and adults to learn about amino acids and proteins, and through Fold-It anyone can design new proteins that have never before existed in Nature!
Recently, the videos below were posted by Brian and his Foldit team at the IPD that explains how you can use Foldit to design proteins that could be used to bind to SARS-CoV-2 particles and inhibit the virus’s infectivity. This video was posted alongside this brief news release that explains more about this really cool project and how you can get started! Enjoy!
Two recent articles have characterized the high-resolution structures of the spike (S) protein of SARS-CoV-2 using cryogenic electron microscopy (cryoEM). The first study published is from Jason McLellan’s group at the University of Texas Austin (see 1st image below), and the second study published is from David Veesler’s group at the University of Washington (see 2nd image below).
These studies give exquisite detail of the SARS-CoV-2 S protein, which is commonly used for vaccine design. The hope is that vaccines can make the human immune system generate long-lived antibodies that tightly bind to the S protein and block the virus from being able to infect and replicate in our cells.
From Wrapp et al. 2020.
From Walls et al. 2020.
Jake is part of a research team at the Institute for Protein Design (IPD) in Seattle that is currently developing a SARS-CoV-2 vaccine with their virus-like particle vaccine platform (see picture at bottom). This work is funded by the Bill & Melinda Gates Foundation and is in collaboration with groups at the Vaccine Research Center at the NIH. Needless to say, it has been exciting and humbling to be a part of a group developing a vaccine that the world badly needs and is demanding in the midst of this unprecedented pandemic.
A few weeks ago, it was surprising when images came out in the media with Trump and Anthony Fauci (head of NIH’s NIAID) alongside a model of the IPD’s influenza vaccine particles. The NYTimes columnist Michelle Goldberg wrote a column on Trump’s calamitous response to the SARS-CoV-2 outbreak that contained the 1st image below. The picture caption originally stated that Trump was being shown a model of a coronavirus, but it’s not a model of a coronavirus — it’s the IPD’s protein nanoparticle with influenza hemagglutinin proteins attached around the particle’s surface. We wrote an email to the NYTimes about this error and they promptly corrected the photo caption! We thank everyone at the NYTimes who make it one of the premier news organizations in the world and operate with the highest levels of integrity and principles.
Photo in NYTimes column that Jake corrected its caption.
The correction posted by the NYTimes.
Another photo that circulated in the media.
A model generated by the CDC of SARS-CoV-2.
An electron micrograph from the CDC of coronavirus particles captured by Dr. Fred Murphy. Each particle is about 100 nm in diameter.
A schematic of the IPD’s protein nanoparticle vaccine platform from Marcandalli et al. 2019.
Michael Emerman, PhD, is one of University of Washington’s leading virologists. Last week, he gave this really nice lecture on SARS-CoV-2 / COVID-19. It’s about 1 hr 20 min, and a great place to start to learn more about the virus (SARS-CoV-2), the disease it causes (COVID-19), and the current pandemic we find ourselves thrust in the middle of and doing everything we possibly can to overcome.
https://research.fhcrc.org/content/dam/stripe/emerman/files/COVID-19%20Lecture.mp4
Enjoy and happy learning!
https://phil.cdc.gov/Details.aspx?pid=23313
Here is a wonderful resource that provides an overview of all things SARS-Cov-2 and COVID-19 in the medical context (biology & medicine, epidemiology, current state of healthcare response, communicating info to others, & practical clinical skills). It’s written by Harvard Medical School students and edited by Harvard professors. It’s a Google Doc, so it will be constantly updated and edited. It’s a great one-stop-shop for all things COVID-19 in a biomedical sense. Enjoy!
