Preventing Pandemics - With a mandate to anticipate next-generation threats, DARPA has helped lay technological foundations for ending COVID-19 ...
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Preventing
Pandemics
With a mandate to anticipate next-generation threats,
DARPA has helped lay technological foundations for ending
COVID-19 and preventing future pandemics
vaccines has been transformational. is a remarkably simple and elegant trial also demonstrated that this new
In 2012 with its ADEPT:PROTECT biological process,” says program type of vaccine could elicit protective
program* (and usually known for short manager Amy Jenkins, who now levels of antibodies in humans.
as ADEPT), DARPA began investing oversees the P3 program along with
in the development of gene-encoded other programs that could transform As the COVID-19 outbreak began early
vaccines, a new category of preventive and empower society’s responses to in 2020, former DARPA performers
measures based on DNA or RNA. DNA infectious-disease threats. and others swiftly adapted their new
is the celebrity biological molecule nucleic acid vaccine platforms to create
that encodes genes; RNA is a related DARPA’s investments in this R&D RNA and DNA vaccine candidates
molecule that shuttles the DNA code space helped to reinforce an entire against SARS-CoV-2. Moderna’s RNA
from the cell’s nucleus to cellular community of nucleic-acid vaccine vaccine was the first COVID vaccine
machinery that converts that genetic
PREVENTING PANDEMICS
researchers and led directly, with to enter clinical trials and advanced
information into proteins that do the the biotechnology firm Moderna in July 2020 to Phase 3 studies in
cell’s work, including neutralizing as a contracted performer on the 30,000 subjects. On December 18,
infectious agents. In this new vaccine ADEPT program, to some of the first 2020, the Moderna vaccine received
strategy — which is at the basis of the experimental vaccines based on FDA Emergency Use Authorization
The public health community has long than years. Now those investments an audacious portfolio of projects highly effective COVID-19 vaccines so-called messenger RNA (mRNA). (EUA) approval for the prevention of
known that pandemics are sure bets, are undergirding history’s most rapid designed to generate pandemic- that have begun to protect millions Initial targets for these new vaccines COVID-19. Inovio, another DARPA
that they are certain to intermittently mobility of innovation for quashing a stopping know-how and to act on that of people — genes that encode included emerging diseases such performer, reported positive findings
visit upon us devastating degrees of raging pandemic. And given the broad knowledge by dramatically reducing the immune-stimulating antigens, such as Chikungunya (ChikV). Moderna for its DNA vaccine, with efficacious
illness, death, and economic loss. The applicability of these technologies, this time it takes to scale-up the means for as the now infamous spike protein subsequently used company funding immune response observed in 34 of 36
current COVID-19 pandemic is just the spate of public-health research will preventing, diagnosing, and treating on the surface of SARS-CoV-2, are to conduct a Phase I clinical trial with (94%) subjects enrolled in the Phase
latest in a series of pandemics that contribute to the desperately needed any infectious disease that might arise, delivered directly to a recipient’s body. 22 healthy volunteers using an mRNA- I safety study. The company initiated
historians have traced back thousands technology base for meeting infectious even ones the world has never seen There, the instructions carried in the encoded ChikV antibody. This marked Phase 2/3 studies to determine
of years. Caused by the severe acute disease threats in the future, whether before. DNA or RNA elicit the body’s own the first safety demonstration of this efficacy and dose protocols on
respiratory syndrome coronavirus-2 they are localized outbreaks or fast- cells to manufacture the antigenic RNA-based medical countermeasure. November 16, 2020.
(SARS-CoV-2), COVID-19 has become growing epidemics and pandemics. The pillars of DARPA’s pandemic viral protein which, in turn, elicits an Moderna reported these promising
the worst pandemic since the flu portfolio fall into the categories immune response to the virus. “This results of its clinical study in 2019. The
pandemic of 1918-1919, which killed Underscoring this point, representatives of prevention, diagnostics, and
tens of millions of people around the Jim Langevin and Elise Stefanik, the treatments.
globe. As January 2021 was coming chairman and ranking member of the
to a close, COVID-19 was closing in House Armed Services Committee’s PATHWAYS TO PREVENTION
on 100 million infections and already Subcommittee on Intelligence and Effective vaccines prevent people from
had surpassed 2.1 million deaths Emerging Threats and Capabilities, getting sick even if they are exposed to
worldwide, including well over 25 note in a joint op-ed published in an otherwise infectious agent, whether
million infections and 420,000 deaths The Hill on May 21, 2020, “DARPA’s it be a seasonal flu virus, the measles
in the United States. investments in biotechnology and virus (Rubeola), or SARS-CoV-2.
pandemic preparedness have given us Vaccines do this by mimicking a viral or
It’s DARPA’s job to anticipate and, if our best chance at developing a rapid bacterial threat in a way that mobilizes
possible, develop technologies for testing and treatment capability for the immune system into behaving as
pre-empting and even eliminating COVID-19. DARPA’s projects aimed to though the host is under attack and
threats that are likely to challenge the revolutionize how our country develops then retaining an ability to counter such
DoD’s ability to carry out its mission in capabilities using the properties of attacks in the future. Conventional
the coming years and decades. With biology to protect our women and vaccines achieve this effect by exposing
our warfighters deploying potentially men in uniform, while simultaneously the immune system to key pathogen-
anywhere in the world, infectious preparing the nation to prevent and borne proteins along with stimulating
disease is prominent among those defend against biological threats.” the immune system (e.g., with
challenges. In the past 15 years, DARPA adjuvant). Nearly all existing vaccine
has stepped up its commitment to Just as massive wildfires can be strategies, however, require laborious,
delivering the scientific understanding prevented by putting out smaller expensive, and lengthy development
and technologies required for fires before they spread, so too can time to counter each new threat.
preventing, diagnosing, and treating localized outbreaks of disease be
infectious disease in timeframes quashed or prevented before they grow This is where DARPA’s groundbreaking A follow-on effort to the ADEPT program, known as the Pandemic Prevention Platform program, aims to take pandemics off of the list of humanity’s angsts
much faster than have been possible into pandemics. With that dynamic with a range of technologies and practices marked by early detection of an outbreak and, within 60 days, development and widescale deployment of protective
push to develop so-called nucleic-acid countermeasures.
so far – weeks and months, rather in mind, DARPA has been managing
In addition to DARPA, the Department (KC10, KC46, KC135, C5, C17, and PATHWAYS TO DIAGNOSIS means that ECHO researchers are
of Health and Human Services (HHS) C130J) were tested within one week on track to delivering diagnostic and
In partnership with prevention,
and the Joint Program Executive Office and USTRANSCOM received valuable prognostic tools that are likely to help
diagnosis is a critical aspect of
for Chemical, Biological, Radiological risk-assessment data by the end of guide individualized quarantine and
pandemic response. Rapid discovery,
and Nuclear Defense (JPEO-CBRND) April 2020 to guide military transport treatment protocols.
validation, and manufacture of
have both invested heavily in clinical safety measures. Commercial aircraft
diagnostic tools that the public-health
development and/or manufacturing to (B737-800, A319, B767-300, and ECHO program performers already
community can use to detect any
bring these nucleic-acid vaccines to the B777-200) were also tested to assess have received EUA approval for a
disease threat, anytime, anywhere
clinic, and – in the case of Moderna’s exposure risk to crew members and direct viral saliva test. This is the first
is the raison d’etre of two DARPA
RNA vaccine – to the American public. passengers. Those studies, coordinated manufacturer’s EUA for diagnosis of
programs: Detect It with Gene Editing
with aircraft manufacturers, involved COVID-19 from saliva. The performers
Technologies (DIGET) and Epigenetic
Another pillar of prevention in public aerosol sources placed in different seat will be submitting an EUA application
CHaracterization and Observation
health is the detection of even low locations to represent “sick” individuals to the FDA in February 2021 for
(ECHO).
levels of disease agents and DARPA and highly spatially-resolved sampling additional host-based diagnostics.
has been developing potentially game- and analysis to map out the movement Meanwhile, DARPA is coordinating
Current diagnostic tools screen blood,
changing technologies in this arena too. of aerosolized particles throughout the further development of the saliva test
saliva, and other body fluids from
The DARPA SIGMA+ program, for one, aircraft. in partnership with NIH’s RADx (Rapid
infected individuals to detect molecular
is on its way to delivering networked Acceleration of Diagnostics) program.
signatures – usually nucleic acids (DNA
sensors that can detect chemical, Testing on military aircraft found
and RNA) or protein – of a virus. With
biological, radiological, nuclear and that smoke barriers offer excellent Somewhat earlier in the DARPA pipeline
DIGET and ECHO, DARPA is supporting
explosive threats. One of the SIGMA+ protection to particle penetration are next-generation diagnostics
innovators whose sights are on new
projects seeks to reduce the time to between cabin zones, especially in the based on CRISPR technology, which
diagnostic technologies that detect
sample and monitor even low levels of KC135, KC46, and KC10. Testing on usually is associated with gene
ultra-low amounts of viral nucleic acid
environmental pathogens from thirty commercial aircraft cabins indicated editing. DARPA program managers are
as well as the subtle but detectable
minutes to a few seconds. In response that even those passengers in instead pursuing it as an approach to
“genetic marks” that past and current
to the pandemic, DARPA program neighboring seats to a “sick” passenger detecting virus-revealing nucleic-acid
infections can leave behind along gene-
manager Mark Wrobel has tasked are at extremely low exposure risk sequences. CRISPR-based diagnostics
carrying chromosomes and that reflect
researchers to update the sensors due to the high air-exchange rates may offer advantages compared to
an individual’s likely response to an
with the ability to identify molecular (25 CFM per passenger), HEPA state-of-the-art technologies. For
infection.
signatures for SARS-CoV-2. This will filtration, and downward air flow. More example, they appear more amenable
open the way to sensor systems that specifically, the analysis suggested to simultaneous analysis of multiple
When the COVID-19 outbreak began
persistently monitor for the virus in that all passengers within 40 rows of pathogens, allowing a single test to
spreading early in 2020, DARPA
large public spaces such as airports, a COVID-19 infected individual in a distinguish, for example, SARS-CoV-2
recognized the potential for the ECHO
transportation hubs, and hospitals. To commercial aircraft (B777-200 and infections from the flu and other
and DIGET programs to aid in the fight
further that cause, DARPA is working B767-300) with the specified HVAC respiratory infections.
against the pandemic through rapid
with researchers in the SIGMA+ settings would experience at least a
and early detection. DARPA program
program to collect additional field data 99.7% reduction in exposure risk (or DARPA also has been supporting other
managers quickly refocused their
and to soon move toward operational 3 orders of magnitude). The average diagnostics-based efforts, including
diagnostic research teams to target
demonstrations of the technology. exposure risk reduction was 99.99% for ones that reveal how the technology
the novel coronavirus as a test of
passengers in the B777-200 and B767- can help move society back toward
their developing technologies. In one
In tandem with this maturing research, 300 while in flight with the specified normalcy. Among these studies is
uplifting result in light of the large
DARPA has initiated the SenSARS HVAC settings. one undertaken with the U.S. Marine
amount of disease transmission from
program to rapidly survey technologies Corps and the Naval Medical Research
symptom-free people infected with
that may provide real-time detection Several commercial aircraft operators Center and known as CHARM, which
SARS-CoV-2, a test developed in the
of SARS-CoV-2 in offices, classrooms, immediately acted on this information stands for COVID-19 Health Action
ECHO program demonstrated 99.1%
conference rooms, and buildings to to minimize exposure risk in their Response for Marines (CHARM). DARPA
accuracy in diagnosing COVID-19. By
help accelerate a safe return to work flights. All of the testing data has been provided near-real-time diagnostic
harvesting specific cells from saliva,
and school for the U.S. population. made available to the public through results for over 3,500 Marine recruits
mucus, or blood, this technology has
With the same view on returning the USTRANSCOM website to help to ensure that training at Parris Island
shown that it is not only possible to
to normalcy, DARPA responded to manufacturers and commercial aircraft could continue through the entirety
diagnose COVID-19 36 hours earlier
a request from the Commander of carriers in their own studies to evaluate of 2020 and into 2021. Data from
than conventional tests, but also that
USTRANSCOM to evaluate the risk countermeasures and risk-mitigation this investigation led to updated CDC
within the first five days of infection,
of aerosol exposure to SARS-CoV-2 strategies for improving the safety of quarantine guidelines that reduced
the severity of a patient’s yet-to-
among individuals in military and passengers during the pandemic. the necessary quarantine period from
show symptoms can be predicted
commercial aircraft. All military aircraft 14 to 10 days for individuals testing DARPA researchers at Vanderbilt University working on antibody discovery.
based on these genetic marks. This
positive for COVID-19, as outlined in a of two antibodies discovered by against COVID-19. The drug Zotatifin, or APIs, which are the critical
November 2020 New England Journal scientists at Vanderbilt University and a protein-synthesis inhibitor identified ingredients for final drug formulations.
of Medicine. licensed by AstraZeneca — entered by Panacea performers with their Under Make-It, researchers automated
large-scale Phase 2/3 clinical studies interactome map, is entering a Phase and expanded production to enable
PATHWAYS TO ANTIBODY- in August and November 2020, 1 clinical trial with investment support the flexible and scalable manufacture
BASED TREATMENTS AND respectively. Based on the results, from the Defense Health Agency. of a broad range of APIs. Current
PROPHYLACTICS bamlanivimab received FDA EUA on efforts focus on addressing regulatory
November 9, 2020, for treatment of It is one thing to discover new approval requirements and adapting
If it becomes too late to prevent recently diagnosed COVID-19 among pharmaceutical treatments; the technology for producing critical
an infection, and if a diagnosis individuals at high risk of developing manufacturing and distributing medicines and precursors needed to
confirms a patient has COVID-19, severe disease. Studies evaluating them in amounts sufficient to treat treat critical-care COVID-19 patients.
then it falls to treatment to save AZD7442’s clinical efficacy are ongoing. everyone who can benefit is another.
the patient and minimize additional Additionally, P3 performers are Indeed, the COVID-19 pandemic has PREVENTING PANDEMICS
transmission. Through novel antibody developing RNA-encoded monoclonal highlighted vulnerabilities in the U.S.
treatments, rapid drug discovery, antibodies targeting SARS-CoV-2 and pharmaceutical supply chain. With When DARPA initiated research on
and domestic manufacture of key are aiming for clinical studies in 2021. its programs aimed at transforming rapid disease response more than a
medicinal compounds known as active how chemists synthesize molecules decade ago, no one could predict what
pharmaceutical ingredients (APIs), Another potential route for rapidly and manufacture chemicals in diseases would emerge and when,
DARPA has been leveraging its ongoing discovering treatments amidst the sufficient quantities, DARPA also is only that they would. Now, the results
research base to hasten the availability sudden arrival of new infectious agents tackling this practical part of outbreak of these DARPA projects are playing
Among the many organ-on-chip modules that have been delivered under the MPS program is this Lung-
of COVID-19 treatments. is to mine already FDA-approved drugs prevention and management. a leading and catalytic role in today’s
on-a-Chip, which was developed by researchers at the Wyss Institute.
(Photo courtesy of the Wyss Institute) for ones that might be repurposed into Under DARPA’s Make-It program, for fight against COVID-19. In typical
A key part of P3, notes program effective treatments. DARPA started example, researchers are developing DARPA fashion, the agency conducted
manager Jenkins, always has from COVID-19 have antibodies in less than 90 days as opposed to the taking steps to make this possible a and commercializing technology technology development efforts years
been to develop antibody-based their blood that bind to SARS-CoV-2. years it previously had taken. decade ago when the agency initiated that directly addresses these supply before they were needed, leading to
countermeasures for preventing In fact, they often have thousands of its MicroPhysiological Systems (MPS) vulnerabilities to enable an end-to-end, high-impact technologies that are key
disease outbreaks from spreading different antiviral antibodies that range As the COVID-19 outbreak began early program. That led to a pathbreaking deployable, and scalable capability for to mitigating the current pandemic.
by treating those who are vulnerable in effectiveness in neutralizing the in 2020, DARPA alerted P3 research drug-screening technology based on the production of medicines made from Perhaps even more consequential is
to exposure — perhaps because virus. By identifying the most powerful teams to be ready to address the human “organ-on-a-chip systems,” readily available ingredients that can the generic nature of many of these
they are in the vicinity of infected antibodies, it is possible to develop novel coronavirus as the next test. which are versatile laboratory be sourced within the U.S. disease-fighting technologies, i.e., the
individuals — with pathogen-stopping targeted and potent antibody-based Once blood samples were recovered surrogates for whole-animal and human applicability to what the World Health
antibodies. “The ability to use these treatments and prophylactics. from some of the earliest COVID-19 clinical tests. Now these commercially- The Make-It technology began taking Organization refers to as “Disease
same preventive antibodies [to treating patients, it took only three weeks for available systems are being used to shape under DARPA’s Battlefield X,” which signifies an infectious and
those who do become infected] is an Years before the current pandemic, potent antibodies to be discovered. rapidly screen drugs to treat COVID-19. Medicine program nearly a decade contagious illness that no one has
awesome side-effect of their utility and DARPA had scored a success in Manufacturing of these antibodies Adding to this drug-screening strategy ago. That program sought to seen before. COVID-19 is just the
so that became a focus for COVID-19 manufacturing an antibody that started soon after that. The first clinical is work in DARPA’s Panacea program establish proof-of-concept for a field- latest Disease X. There will be more
because we had few other treatment binds to the Ebola virus. It became trial of a P3-discovered antibody that yielded the first published human/ deployable pharmacy kit to assist of them and DARPA’s extensive and
options,” said Jenkins. the basis of one of the two approved product began on June 1, 2020 – SARS-CoV-2 protein interactome map. military medical personnel treating continuously growing platform of
Ebola treatments and is a large part under 90 days from receipt of the first This data-rich tool describes how service men and women in forward pandemic-stopping technologies
More specifically, a primary treatment of the reason why Ebola is becoming a blood samples. Two additional P3- the proteins in and on SARS-CoV-2 operations. Researchers in the program – spanning from prevention to
and prophylaxis strategy DARPA is manageable infectious disease rather discovered antibodies were combined particles interact with human cells and demonstrated the ability to produce diagnostics to treatment – will be ready
pursuing capitalizes on the successful than one dreaded for its pandemic into a “cocktail” or combination it has been used worldwide in the fight four active pharmaceutical ingredients, to use in humanity’s defense.
immune responses of people who have potential. However, the actual Ebola product, and this treatment entered
recovered from COVID-19. When people antibody-discovery work, performed clinical studies in August 2020. HHS
fight off a viral infection, their immune by the National Institutes of Health, and JPEO-CBRND have both invested
systems manage to identify and then took years. In FY2016, DARPA initiated significant funds with major drug
mass-manufacture antibodies. These the P3 program aimed squarely at manufacturers to make and test P3-
are specialized protein molecules with the rapid discovery, testing, and derived antibody products.
astonishing abilities to specifically bind manufacture of antibody treatments
to molecular motifs on pathogenic to fight any emerging disease threat. Following successful Phase 1 clinical *Autonomous Diagnostics to Enable
particles such as viruses. That antibody Using influenza, Zika, and MERS safety trials, both of these antibody Prevention and Therapeutics (ADEPT):
response hobbles the virus particles (Middle East Respiratory Syndrome) products – bamlanivimab, the antibody Diagnostics on Demand (DxOD);
and flags them for destruction by as test cases, researchers in the P3 discovered by AbCellera Biologics and Prophylactic Options to Environmental
other components of the immune program demonstrated how to find and licensed by Eli Lilly; and AZD7442, An organ-on-chip module developed by the Wyss Institute undergoes testing. and Contagious Threats (PROTECT)
system. Those who have recovered manufacture neutralizing antibodies in the combination product comprised (Image courtesy of the Wyss Institute)
A researcher from the University of Nebraska Medical Center suits up to
collect samples from a COVID-19 patient.
www.darpa.mil
Latest revision on 1/29/2021
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