Scientists To Stop COVID19 2020-04-23 FINAL
Scientists To Stop COVID19 2020-04-23 FINAL
We are a group of passionate citizen-scientists who offer four actionable, non-partisan proposals to
produce safe and effective COVID-19 therapeutics and vaccines in the shortest possible timeframe, and
to reopen our society in a manner that reduces the risk of future COVID-19 outbreaks. None of the
contributors named in this proposal have any direct or known indirect financial interests in the referenced
companies. Our only motivation is to help defeat the serious threat our nation and the world now faces.
The war against COVID-19 is being fought on multiple fronts: by our heroic healthcare workers on
the front lines; by talented scientists in the laboratories of corporations and research institutions; by
governments at the federal, state, and local levels; and by other citizens sacrificing their freedoms to limit
the spread of the pandemic. Here we describe plans to develop therapeutics and vaccines, and to reopen
our businesses and schools, that could be deployed in several waves.
We envision a first wave of therapies using existing drugs that will establish a beachhead in the
fight against the virus (testing in April-May 2020, use immediately afterwards). A second wave of potent
new antibody drugs developed specifically to neutralize COVID-19 offer a promising combination of
speed, safety, and likelihood of being effective (testing in June-August 2020, use afterwards). A third
wave of vaccines for long-term victory over the virus will offer seasonal or multi-year immunity to
COVID-19 (testing in March 2020-March 2021, use afterwards). In parallel, reopening of businesses
and schools to restore our society and economy (implementation in May-June 2020, lasting until the
threat has passed) will use science-driven symptom reporting, virus testing, and personal protective gear
to minimize future COVID-19 outbreaks and additional loss of life.
The four proposals that follow describe: (1) How to rapidly repurpose an antiviral drug to treat
COVID-19 patients; (2) How to expedite the development of human antibody drugs to treat patients and
to provide short-term protection for healthy individuals; (3) How to develop COVID-19 vaccines on an
expedited time scale; and (4) How to reopen our businesses and schools in a manner that reduces the risk
of future outbreaks and deaths.
It is critical that approaches to drugs, vaccines, and reopening our society be pursued and
supported simultaneously. To defeat this novel coronavirus in the United States, and around the world,
will require a massive and well-organized collaborative effort from government, industry, philanthropy,
and citizens. It is vital that we establish these partnerships and take actions immediately.
We hope these proposals will be considered with the seriousness and speed required by the current
circumstances.
Sincerely yours,
Dr. Lynn Goldman, M.D., M.S., M.P.H. Dr. Stuart Schreiber, Ph.D.
Dr. Michael Z. Lin, M.D., Ph.D. Dr. Ramnik Xavier, M.D., Ph.D.
None of the named contributors is aware of any direct financial interest in the companies mentioned herein
and none receives compensation of any kind for his or her participation.
Contributors
Dr. Thomas J. Cahill, M.D., Ph.D. is the Founder and Managing Partner of Newpath Management, L.P.
Dr. Cahill received both his M.D. and Ph.D. from Duke University. His Ph.D. work, with Professor Robert
Lefkowitz (Nobel Laureate), focused on studying cellular receptors and their signaling to inform novel drug
development and discovery.
Dr. Benjamin Cravatt, Ph.D. is a Professor of Chemistry at The Scripps Research Institute in La Jolla,
California and a member of the National Academy of Sciences. He is a founder of Vividion Therapeutics,
Abide Therapeutics, and ActiveX Biosciences. Considered a co-inventor of activity-based proteomics,
Cravatt is a prominent figure in the field of chemical biology.
Dr. Lynn R. Goldman, M.D., M.S., M.P.H. is the Dean and Professor of Environmental and Occupational
Health at the Milken Institute School of Public Health at the George Washington University. She is a
member of the National Academy of Medicine, the National Research Council Strategic Planning Group,
and the NIH National Advisory Environmental Health Sciences Council.
Dr. Akiko Iwasaki, Ph.D. is a Professor of Immunobiology at Yale University School of Medicine, and a
Howard Hughes Medical Institute Investigator. She is a member of the National Academy of Sciences, and
a member of the National Academy of Medicine. She has discovered molecular mechanisms underlying
innate and adaptive antiviral immunity and is a pioneer of novel vaccine strategies.
Dr. R. Scott Kemp, Ph.D. is an Associate Professor and Director of the Laboratory for Nuclear Security
and Policy at the Massachusetts Institute of Technology. Dr. Kemp works on the scientific foundations of
U.S. national security policy.
Dr. Michael Z. Lin, M.D., Ph.D. is Associate Professor of Neurobiology, Bioengineering, and Chemical
and Systems Biology at Stanford University. A NIH Pioneer Award recipient, Dr. Lin develops protein-
based tools for molecular imaging and control of gene and viral therapy.
Dr. David Liu, Ph.D. is Professor of Chemistry and Chemical Biology at Harvard University, Vice-Chair
of the Faculty at the Broad Institute of MIT and Harvard, and a Howard Hughes Medical Institute
Investigator. He is a founder of Beam Therapeutics, Editas Medicine, Prime Medicine, Pairwise Plants, and
Exo Therapeutics. Liu is a pioneer in chemical biology, protein engineering, and gene editing, and has
developed technologies such as base editing and prime editing.
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Dr. Michael Rosbash, Ph.D. is the 2017 Nobel laureate in Physiology or Medicine, a member of the
National Academy of Sciences, a Professor of Biology at Brandeis University, and a Howard Hughes
Medical Institute Investigator. Rosbash is a pioneer of chronobiology, the study of how living systems sense
and respond to time.
Dr. Stuart Schreiber, Ph.D. is a Professor of Chemistry and Chemical Biology at Harvard University and
co-Founder of the Broad Institute. He is a member of the National Academy of Sciences, and a founder of
Vertex Pharmaceuticals, Ariad Pharmaceuticals, Infinity Pharmaceuticals, Forma Therapeutics, H3
Biomedicine and Jnana Therapeutics. Schreiber co-pioneered the field of chemical biology.
Dr. Edward Scolnick, M.D. is the former Head of Research and Development at Merck and a core
investigator at the Broad Institute of MIT and Harvard. While at Merck, Scolnick oversaw the development
of 28 FDA-approved drugs and vaccines, including statins, HIV protease inhibitors, and Gardasil. He also
made seminal discoveries on the nature of genes that cause cancer in humans before beginning his 22-year
career at Merck.
Dr. Jonathan W. Simons, M.D. is the CEO and President of the Prostate Cancer Foundation. Simons a
molecular oncologist who previously was the Founding Director of the Winship NCI Cancer Center at
Emory University, and currently co-directs the PCF-Veterans Administration Precision Oncology Program
for Prostate Cancer.
Dr. Ramnik Xavier, M.D., Ph.D. is Professor of Medicine at Harvard Medical School, former Chief of
Gastroenterology at Massachusetts General Hospital, Director of Computational and Integrative Biology,
MGH, and a core institute member of the Broad Institute of MIT and Harvard. He has discovered molecular
mechanisms underlying innate and adaptive immunity, as well as causes of Crohn’s disease, ulcerative
colitis, and autoimmunity.
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INDEX
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I. FIRST WAVE: REPURPOSED DRUGS
Plan to prepare for immediate provisional use of a repurposed antiviral drug to treat COVID-19
Among potentially effective and safe COVID-19 treatments, repurposed drugs and drug candidates can be
deployed in the shortest possible timeframe. Some of these repurposed drugs and drug candidates have
already garnered promising data, including antivirals such as remdesivir, niclosamide, favipiravir, and
camostat, as well as drugs that alleviate the excessive inflammation that can cause death, such as
tocilizumab. In addition, novel therapeutic modalities, such as Alnylam’s use of RNA silencing molecules
to destroy viral RNAs that are essential to the SARS-CoV-2 life cycle, are also promising and offer unique
strengths, although most novel modalities will require additional time for validation in animals before
clinical trials can begin. A fairly comprehensive list of potential COVID-19 therapies is maintained by the
Milken Institute: https://milkeninstitute.org/covid-19-tracker.
Prioritization will be necessary to widely deploy any repurposed drugs on a greatly accelerated time scale.
Among promising repurposed drugs and drug candidates, remdesivir has emerged as one leading candidate.
Here, we present evidence for remdesivir’s efficacy and safety, and propose how to accelerate its approval
and use to treat COVID-19. Many of our suggestions, while presented for remdesivir, are also
applicable to other drug candidates.
COVID-19 is caused by the virus SARS-CoV-2. The genome of SARS-CoV-2—the genetic instructions
required for its life cycle—is a single strand of RNA. A viral enzyme called RNA replicase must copy this
strand of RNA in order for the virus to replicate. This enzyme does not exist in humans, and thus drugs that
inhibit RNA replicase could effectively treat COVID-19 without harming patients. A similar strategy of
inhibiting a viral replicase was effectively used to treat HIV.
As detailed below, given its favorable safety profile and preliminary evidence of efficacy, we believe it is
essential to plan now to facilitate the use of remdesivir to treat COVID-19. We propose the following:
• FDA should coordinate with Gilead, the maker of remdesivir, to receive the results of their clinical
trials as they come in, rather than wait for submission of a new drug application (NDA). NDA
preparation often takes months after clinical trials are complete. FDA can dramatically shorten the
process by examining the data themselves directly in real time without requiring NDA paperwork.
If the results are clearly positive, then provisional approval can be granted.
• The government should take steps to facilitate large-scale manufacturing of remdesivir by other
U.S. drug companies in addition to Gilead. For example, the government could identify companies
with manufacturing capabilities suitable for remdesivir synthesis at scale and begin discussions with
those companies to clear any regulatory hurdles needed to repurpose those capabilities for
remdesivir production.
• Both of these steps are similar to what we have already recommended for monoclonal antibody
therapy (see the proposal below).
• Remdesivir is being tested in multiple COVID-19 clinical trials. The drug is given intravenously,
and the initial dose is 200 mg followed by 100 mg for 5-10 days. We believe this dose may be too
low and treatment should be administered earlier in symptomatic patients. Whether higher
doses could be given safely can be determined by examining the animal safety studies carried out
by Gilead. If these studies do not reveal a potential safety issue at higher doses, then higher doses
should be given as early as possible during infection. We speculate that the current dose is chosen
because of limited supplies. We urge the government to determine the facts around this issue so
optimal trial doses for efficacy can be determined.
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• An inhaled form of remdesivir (instead of intravenous) is important so that treatment can be
administered remotely and more widely. Government should push the development of inhaled
formations of remdesivir. Companies including GlaxoSmithKline and AstraZeneca have experience
in this area and might be helpful.
Below we present recent evidence from peer-reviewed publications that suggests remdesivir may turn out
to be effective and safe for COVID-19. Knowing how to most effectively and safely use remdesivir to
treat COVID-19 will require properly designed randomized, controlled trials in actual patients.
• A 2016 Nature article showed that remdesivir inhibits viral RNA replicases and is safe and effective
in monkeys infected with Ebola virus (which, like SARS-CoV-2, is an RNA virus). At the highest
dose of remdesivir, monkeys were completely protected from death caused by Ebola virus. Ebola virus
infection is very rapid in Monkeys and the best results were observed when the drug was given early
after infection. Early treatment with remdesivir, versus later in disease course, will also likely be
a key determinant for success with coronavirus.
• A 2017 Science Translational Medicine article showed that remdesivir was effective against
coronaviruses, the family of RNA viruses to which SARS-CoV-2 belongs. Importantly, remdesivir was
shown to inhibit SARS-CoV-1, whose RNA replicase is 96% identical to that of SARS-CoV-2; SARS-
CoV-1 causes SARS through a process essentially identical to severe COVID-19 cases. Remdesivir
potently inhibited pathogenic coronaviruses in cultured human lung cells with a therapeutic index of
over 100, meaning that the dose required to stop the virus was at least 100 times lower than the dose
required to show toxicity to cultured human lung cells. This study also showed that remdesivir inhibited
SARS-CoV-1 replication in lungs of infected mice.
• Remdesivir has already been shown to be safe in humans. In a trial of Ebola patients described in
2019, remdesivir did not show any noted toxicity. Safety is the primary barrier to wide use of any
experimental drug, and this trial proved remdesivir can be safely used in humans (Mulangu et al., New
England Journal of Medicine 2019).
• Remdesivir can be dosed to sufficient concentrations to have antiviral effects. In this same 2019 study,
it was effective at reducing Ebola virus levels. Ebola virus is not a coronavirus, but this result
demonstrates that remdesivir can reach concentrations in humans that have an antiviral effect.
• We believe too low a dose of remdesivir was used in the Ebola trial. A dose of 10-20 mg/kg should
be considered in the current clinical situation. We elaborate on this point later in this memo.
• In monkeys infected with SARS-CoV-2, remdesivir inhibited viral replication and reduced lung damage
(de Wit et al., PNAS 2020).
• In human cells in the lab, remdesivir inhibits replication of SARS-CoV-2, the virus causing COVID-
19. (Williamson et al. doi: 10.1101/202004.15.043166)
• Remdesivir has already been given on a compassionate use basis to many COVID-19 patients, and a
case report exists (e.g., Holshue et al., New England Journal of Medicine 2020). No major adverse
effects have been reported, suggesting that remdesivir is safe in COVID-19 patients.
• Knowing how to safely and effectively use remdesivir to treat COVID-19 requires properly
designed, randomized, and controlled trials in patients.
There are over 20 remdesivir trials currently in progress worldwide. We note the first two randomly
controlled trials in China were prematurely terminated due to lack of patients, and the clinical context or
patient profile of these trials may differ from those of other trials. It is important to continue existing
remdesivir trials to obtain a more complete understanding of remdesivir’s potential efficacy.
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In assessing the potential widespread use of remdesivir in infected patients, certain points are critical:
1. The proper dose of the drug needs to be determined. FDA previously limited the dose based on
reversible liver function tests; an increase in dose may be possible without compromising safety.
2. Based on experience with other antiviral medications, it seems likely that administering the drug as
early in infection as possible will be more helpful than if administered later.
3. Supply of the drug is crucial. We speculate that the low dose used in the Ebola trial was chosen based
upon a limited supply. The government needs to determine how quickly millions of doses can be
manufactured and whether contract companies need to bolster what Gilead can do in their own
manufacturing facilities. Gilead has recently released a letter underlining the limited doses that will be
available. Gilead is ramping up their production capabilities. However, their estimate of how many
patients can be treated will depend upon a future determination of optimal dose.
It is important to understand both the benefits and limitations of remdesivir compared to other therapeutic
options, including the neutralizing human monoclonal antibodies we recommended in our first proposal.
Based on the experience with Ebola (Mulangu et al., New England Journal of Medicine 2019), remdesivir
is unlikely to be more effective for treating COVID-19 than the best monoclonal antibodies currently under
development. However, monoclonal antibodies will not be available for a few more months, and for this
reason we consider them part of a second wave of therapies entering clinical trials in the summer (see the
second proposal in this set). A first wave of therapies can only come from repurposed drugs. Moreover,
since neutralizing monoclonal antibodies function by a distinct mechanism, it is possible that the
combination of monoclonal antibodies and remdesivir will be an even more effective second wave therapy
than either single agent alone.
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II. SECOND WAVE: ANTIBODY THERAPIES
Plan for development of an antibody therapy and short-term vaccine by Fall 2020
American biotechnology companies have already cloned antibodies against COVID-19 virus from
recovered patients and mice with human immune systems, and determined which antibodies are especially
effective at neutralizing the virus in petri dish experiments. These monoclonal antibodies can now be used
both to prevent COVID-19 like a short-term vaccine, and to treat COVID-19 patients.
Two American companies (Regeneron Pharmaceuticals and Vir Biotechnology) are leaders in the
monoclonal antibody space. Both of these companies have (1) a proven track record of developing similar
therapeutics on expedited timelines (i.e., for Ebola virus); (2) development timelines for COVID-19
therapeutic candidates that are leading the industry; and (3) manufacturing capabilities to enable 100% of
their production be done in the United States. Although other COVID-19 therapeutic strategies must be
advanced in parallel, we consider these monoclonal antibodies to have the highest likelihood of succeeding
for the following reasons.
To accelerate the testing, approval, and distribution of monoclonal antibodies against COVID-19, there
must be regulatory flexibility and focused efforts to eliminate all avoidable bottlenecks via the
following steps:
• These companies will be submitting investigational new drug (“IND”) applications to initiate clinical
trials to the FDA in the near future. We suggest the WH and FDA leadership work directly with
these companies on a regular or daily basis. The WH can then ensure that the FDA asks all its
questions to these companies before receiving the IND. Standard rules are that companies must wait 30
days after submitting an IND before initiating trials. We recommend that the FDA allow trial initiation
immediately upon IND receipt as their questions will have already been answered. Desired timeframe:
April-June 2020.
• The FDA should allow, encourage, and facilitate the task of scaling up production of COVID-19
treatments prior to final approval; this is, of course so that treatments can be broadly available to the
public the day of approval. For example, the FDA could quickly approve new or overseas plants for the
production of other medicines, so that U.S. plant can be devoted entirely to manufacturing COVID-
19 treatments. Similar manufacturing assistance should also be offered to all U.S. companies well-
positioned to pursue the monoclonal antibody approach. All other rate-limiting manufacturing issues
should be addressed now. If the above steps occur expeditiously, it should be possible to manufacture
antibodies for COVID-19 at a scale sufficient for widespread deployment in the late summer or early
fall of 2020. Desired timeframe: June-August 2020.
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• Engage other large U.S. biomanufacturers to contribute their capacity to the manufacturing effort,
to further expedite broad availability upon FDA approval. Desired timeframe: June-August 2020.\
• Clinical trials usually begin with a small safety trial in a small number of people. We suggest
monoclonal antibody treatments be allowed to proceed directly to a larger efficacy trial (e.g., by
employing dose-titration in infected individuals, etc.) with enough patients to reveal how well the
antibodies work, ideally both as a treatment and as a short-term vaccine. Scientists and physicians have
enough experience with other virus-neutralizing antibodies to know the dose required. Safety will be
confirmed simultaneously in this efficacy trial. Desired timeframe: June-August 2020.
• Following a successful clinical trial, a company reports the results and formally submits a new drug
application (“NDA”). FDA review of an NDA normally takes 9-12 months. Given the state of the
pandemic, we recommend that the FDA communicate daily with these companies during preparation
of the NDA to assure all required components are included, and then complete the NDA review within
1 week of receipt since its questions will have already been answered prior to submission. Desired
timeframe: August-September 2020.
• Given the efforts outlined above to preemptively mass-produce treatment in advance of the clinical trial
outcome, broad administration can begin both as a treatment (prioritizing critically ill patients) and as a
short-term vaccine immediately upon FDA approval. Desired timeframe: August-September 2020.
Timeline summary:
• By June 2020: investigational new drug application submitted and reviewed; efficacy clinical trials
begin.
• June to August 2020: manufacturing ramp-up and antibody production for broad and nationwide
administration.
• August 2020: Proof of efficacy in preventing infection and/or treating disease obtained from clinical
trials; if positive, as anticipated, very rapid FDA approval of a new drug application.
• August-September 2020: broad administration of antibodies to the ill and to critical healthy
individuals. We believe monoclonal antibodies will make a major contribution to preventing a second
wave of disease in the fall, which could impede our societal and economic recovery.
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III. THIRD WAVE: VACCINES
Plan for rapid development of a vaccine against COVID-19 and future pandemics
As with many other infectious disease epidemics, long-term control will require the development and
implementation of an effective vaccine that can provide population-wide immunity against the pathogen.
This third wave vaccine-based approach will establish long-term victory over the virus. Historically,
the average time for new vaccine development and approval is six to eight years. The current unprecedented
nature of the COVID-19 pandemic requires immediate and unique action. Some approaches currently being
pursued include inactivated virus particles (Sinovac), recombinant proteins (Sanofi), live hybrid viruses
(Janssen), and RNA-based vaccines (Moderna, CureVac, BioNTech/Pfizer, Translate/Sanofi). More than
90 vaccine development efforts are listed at https://milkeninstitute.org/covid-19-tracker. It is not known yet
if vaccines will need to be seasonal, as with influenza, or will provide durable long-term immunity, as with
measles. Timeframe: testing in March 2020-March 2021, use afterwards.
• We propose that the federal government appoint an empowered council that will work with U.S. and
global stakeholders to coordinate the required development and investment actions in an efficient, time-
sensitive, and non-partisan way.
• The effectiveness and safety of a SARS-CoV-2 vaccine candidate can only be assessed by clinical
study. Given the urgency of the SARS-CoV-2 pandemic, it is essential that a standardized clinical
assessment approach be devised and supported by regulators to enable the rapid and
meaningful comparison of data sets.
• Given the increasing number of stakeholders involved in the COVID-19 vaccine effort, we are
concerned that the effort will become diffuse and will not achieve the level and degree of focus required
for a sufficiently swift pandemic response. Thus, unprecedented transparency and end-to-end
coordination are required. The council should coordinate all aspects of the development and delivery
of a vaccine among developers, regulators, funders, and other global stakeholders.
• Plans must be put in place to distribute and administer the vaccine. This effort should build upon actions
to expand the public-health workforce supporting widespread testing and tracing. Public communication
will be critical to educate the public about the benefits and risks of vaccination of all individuals,
including children; the benefits will strongly outweigh the risks for an approved vaccine. Too many
different COVID-19 vaccines on the market could create confusion that will not support
implementation.
The proposed centralized approach has proven effective in the past while responding to global emergencies.
A similar approach effectively accelerated the development of a polio vaccine in the 1950s. In this
celebrated case, the private National Foundation for Infantile Paralysis (later known as the March of Dimes)
provided centralized funding and technical decision-making to ensure the development and availability of
a vaccine for what was at the time a devastating infectious disease. The same focus is now required to
confront the current pandemic.
Manufacturing investments are substantial and, accordingly, will likely be made by governments or large
funding organizations. We must focus on manufacturing an effective vaccine at a scale that will permit
world-wide use. In a typical vaccine development program, investments in scale-up and manufacturing are
tied to an increasing understanding of a given vaccine’s clinical potential. Such a measured approach is not
viable for SARS-CoV-2 because of the urgency. Large at-risk development decisions will need to be
made, for each individual promising vaccine candidate, well before significant clinical data become
available. However, given the scale of the at-risk investments, the number of vaccine approaches in which
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such investments can be made will necessarily be smaller than the much larger number of all SARS-CoV-
2-related vaccine R&D efforts.
At present, the non-company funding sources for the large majority of SARS-CoV-2 vaccine efforts
globally include the Coalition for Epidemic Preparedness (CEPI), the Biomedical Advanced Research and
Development Authority of the U.S. government (BARDA), the Bill & Melinda Gates Foundation (BMGF),
and an increasing number of sovereign country governments. CEPI (www.CEPI.net) is funded by the
BMGF, the Wellcome Trust, and several European governments. BARDA is a part of HHS and is fully
funded by the U.S. Government. BMGF is the world’s largest private charity. Among these three largest
funders, an effort is ongoing to coordinate their support in a way that will allow for efficient decision making
and use of available funds for at-risk investment and development support.
Such coordination requires centralized decision making to manage the activities across multiple individual
promising approaches, and among the supporting functional and funding efforts—thus our recommendation
to appoint an “empowered council”. A prospective agreement must be established primarily among the
regulators, the key funders, and key global stakeholders to ensure that the empowered council has the
authority to direct the overall enterprise. The empowered council should have a strong technical/scientific
background with direct experience in the previous development of infectious disease vaccines. Such a
central coordinating and decision mechanism can ensure alignment among regulatory requirements for
clinical and pre-clinical evaluation of vaccine candidates and can effectively manage the large at-risk scale-
up and manufacturing investments needed to ensure ready availability of a vaccine as soon as its safety and
efficacy has been demonstrated. It can also manage the complexities of the multiple parallel technical
approaches that will be required.
Over the years, vaccine R&D for other human and animal pathogens have led to the development of a
number of different “vaccine platforms,” most of which can potentially be adapted for the design of a
potentially effective vaccine against SARS-CoV-2. Many organizations and companies are currently
involved in designing various vaccine approaches using either internal funding or funding from various
support sources (see later). Among these efforts, Moderna’s RNA-based vaccine has already commenced
clinical trials, and whether subjects create protective antibodies will be assessed in the next few months.
However, whether this vaccine safely prevents disease may take longer to assess, and Moderna does not
anticipate widespread implementation for at least 12 months. We recommend a centralized approach to
manage the anticipated flow of clinical data as various vaccine candidates are evaluated. Such a
standardized approach will support rapid progression to clinical trials in a way that will yield the relevant
comparative safety and efficacy data in as short a period as possible, allowing for potential rapid
deployment.
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IV. RESTORING OUR SOCIETY AND ECONOMY
A COVID-19 Risk Reduction Plan for Reopening Schools and Businesses
While drastic social-distancing and lock-down measures remain a necessary step to disrupt the exponential
spread of COVID-19 in the United States, restoring our society and economy is increasingly urgent for the
welfare of many Americans. In this document we propose a plan for returning people to schools and
businesses in a manner that reduces the risk of future COVID-19 outbreaks and loss of life, for example
from a “second wave” of the disease in the fall.
Once current social-distancing measures are lifted, the current policy of testing only symptomatic
individuals cannot adequately curtail COVID-19 transmission. For example, a study of COVID
transmission in Wuhan, China occurring between February 1 and March 12—when Chinese health officials
were carrying out house-to-house temperature checks on the general population—found that even with such
intrusive measures 86% of COVID cases were not identified, likely because the majority of infected persons
had mild symptoms.1
In this proposal, we describe a policy that requires individuals returning to schools and work to take three
key steps: 1) to report symptoms daily before working; 2) to participate in frequent virus (PCR) testing; and
3) to wear certain personal protective equipment (PPE). We assess that this policy will substantially reduce
the risks associated with reopening our society and restoring our economy, thereby protecting our recovery.
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(95%CI 7.8%–54%).5 Another study using data from the Diamond Princess cruise ship (which had an age
distribution skewed older than the general population) estimated that 18% (95%CI: 16–20%) of infected
persons remain asymptomatic, subject to assumptions about the incubation period.6 In contrast, a third study
of 4,950 close contacts found that only 6.2±2.2% of infected persons were fully asymptomatic throughout
the course of the disease, but that an additional 38±5.4% showed only mild symptoms and may not have
considered themselves to be infected.3
These data emphasize the importance of respondents giving accurate answers to survey questions and using
centralized algorithms, rather than individual judgment, to make decisions about who can engage in work
and school activities. A variety of strategies can be used to increase compliance, including assurances of
pay while at home with symptoms. The calculated risk threshold can be set by governments and adapted to
respond to real-time epidemiology.7
We also considered the use of fever screening devices that rapidly measure the temperatures of people at
the entrances to schools and businesses. However, we are concerned that questions about the accuracy of
this method, the availability and cost of fever screening devices at the scale needed, and the fact that fever
screening assesses only one COVID-19 symptom may limit its practical usefulness in the current situation.
Whether fully asymptomatic COVID-19 cases pose an infection risk to others remain to be seen. We are
only aware of one study that examined this question, but the statistical uncertainties were too large to make
a useful deduction of the asymptomatic carrier risk.3 However, because asymptomatic case fractions may
be large, and because even symptomatic cases may be contagious prior to the onset of symptoms, frequent
virus testing to detect viral presence is essential, in addition to a daily survey of symptoms.
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leak-tight fit and proper use, which is difficult to maintain outside a trained user cohort.13 Controlled
comparisons of surgical masks and N95 respirators in real-world settings of occasional exposure have found
them similarly effective in reducing respiratory infections.14 Surgical masks therefore strike an optimal
balance between availability and practical effectiveness for most people.
In contrast, cloth masks were reported to be 63% as effective as surgical masks in preventing any respiratory
symptoms for the wearer, and only 8% as effective in preventing influenza-like illness.14 As such, we
recommend that wearing surgical masks (or, for high-exposure settings, N95 respirators with
appropriate training), rather than cloth masks, be required for entering schools and businesses. We
note that studies on the lifetime of coronaviruses on surfaces including paper15 suggest that if masks are in
limited supply, reusing masks that have been stored away from human contact for 5-7 days may pose
minimal additional risk.
Gloves can also lower infection risk, offering an odds ratio of 0.43 (95%CI: 0.29-0.65) in a hospital
setting.13 They could also be required, although proper use habits are needed for gloves to be effective. We
anticipate that many people not accustomed to the uses of gloves for biomedical purposes will contaminate
themselves, surfaces, or others through improper use.
References Cited
1. Li, R. et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2).
Science eabb3221 (2020) doi:10.1126/science.abb3221.
2. Liu, Y. et al. Viral dynamics in mild and severe cases of COVID-19. The Lancet Infectious Diseases S1473309920302322
(2020) doi:10.1016/S1473-3099(20)30232-2.
3. Luo, L. et al. Modes of contact and risk of transmission in COVID-19 among close contacts.
http://medrxiv.org/lookup/doi/10.1101/2020.03.24.20042606 (2020) doi:10.1101/2020.03.24.20042606.
4. Wölfel, R. et al. Virological assessment of hospitalized patients with COVID-2019. Nature (2020) doi:10.1038/s41586-
020-2196-x.
5. Nishiura, H. et al. Estimation of the asymptomatic ratio of novel coronavirus infections (COVID-19). International
Journal of Infectious Diseases S1201971220301399 (2020) doi:10.1016/j.ijid.2020.03.020.
6. Mizumoto, K., Kagaya, K., Zarebski, A. & Chowell, G. Estimating the asymptomatic proportion of coronavirus disease
2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Eurosurveillance 25,
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