THE NEED AND OPPORTUNITY

A primary objective of DARPA’s Biological Technologies Office (BTO) is to better ensure the health, and thereby the force readiness, of the country’s military service community. The COVID-19 pandemic, which rapidly spread worldwide from an initial outbreak in China at the end of 2019, highlights one of the most perilous vulnerabilities to deployed military personnel and civilians: lack of protection and medical countermeasures (MCMs) against endemic and emerging biothreats. The Zika outbreak in 2015-2016, the more recent Ebola outbreak in the Democratic Republic of Congo, and mosquito-borne viruses such as Chikungunya and Dengue are among these threats.

Vaccines are the traditional mainstay of long-term infection prevention, while antibody approaches have at times been used to treat active infections. In one antibody-based approach that is being applied on a small scale in the current pandemic, blood serum with presumably protective antibodies obtained from those who have recovered from an infection is infused into patients. In more recent decades, monoclonal antibodies manufactured in cultured immune-system cells have been used to treat certain cancers and immune disorders. However, these treatments have suffered from shortcomings – including slow development, expensive manufacture, and dependence on continuous cold storage – that have prevented widespread use by the military.

THE DARPA SOLUTION

In 2012 with the ADEPT:PROTECT program*, DARPA began investing in the development of gene-encoded vaccines, a new category of preventive measures based on DNA or RNA. In this approach, genes that encode immunestimulating antigens, such as the spike proteins on the surfaces of viruses like the one (SARS-CoV-2) that causes COVID-19, are delivered directly to a recipient’s body. There, the instructions carried in the DNA or RNA elicit the body’s own cells to manufacture the antigenic viral protein, which, in turn, elicits an immune response to the virus.

Gene-based vaccines have shown great promise as a means to provide safe, reproducible, long-term immune protection. For vaccines to work, however, they often require more than one dose and it often takes weeks to months before a recipient’s immune system builds up sufficient protection again the vaccine’s viral target. With these biomedical realities come threats to warfighters if they deploy to pathogen-rife regions before having established relevant immunity and threats to military missions due to delayed deployment of personnel until they achieve immune protection.

For a vaccine to confer immunity, it must lead to the production within a recipient of highly potent antibodies that can neutralize the pathogen. DARPA initiated the ADEPT:PROTECT program (most often referred to more simply as ADEPT) with the intention of bushwhacking a novel pathway to near-immediate protection against pathogens for which vaccines are not yet available and to confer interim-term protection during the development of a vaccine, which can take years.

THE IMPACT

DARPA’s investments in this space led directly, with the biotechnology firm Moderna as a contracted performer on the program, to a first-ever human clinical trial with an RNA vaccine in 2019.

Earlier proof-of-concept experiments funded under ADEPT primarily with 6.1 funding (for basic research) demonstrated that delivery of antibodymaking instructions — by way of messenger ribonucleic acid (mRNA), deoxyribonucleic acid (DNA), or another genetic-information-carrying tactic that relies on small viruses known as adenovirus-associated viruses (AAVs) — led to the production of antibodies that conferred protection in test animals exposed to the mosquito-borne Chikungunya (ChikV) virus.

In a more applied phase of technology development, Moderna was converted to 6.2 funding (applied research) to begin pre-clinical studies in nonhuman primates with an RNA-encoded antibody against ChikV and to produce the countermeasure using Good Manufacturing Practices (GMP), which regulatory agencies such as the Food and Drug Administration often require.

Moderna subsequently used company funding to conduct a Phase I clinical trial with 22 healthy volunteers using an mRNA-encoded ChikV antibody. This marked the first safety demonstration of an RNA-based medical countermeasure. Moderna reported these promising results of its clinical study in 2019. The trial demonstrated platform safety as well as the ability to generate protective levels of functional antibody in humans. In response to COVID-19, Moderna in March 2020 initiated human trials of gene-encoded antibodies that target SARS-CoV-2.

Research by Moderna and other ADEPT performers has provided proof-ofconcept results that simultaneously delivering gene-encoded antibody treatment and vaccine confers the recipient with immediate immune protection while a long-term immune response develops.

LOOKING AHEAD

DARPA’s R&D investments to de-risk the pathway to gene-based medical countermeasures have spurred likeminded innovators. In addition to Moderna, several other companies, including AstraZeneca and Inovio, have made major investments in this budding biomedical field. These DARPA investments also spurred the biotech firm RenBio to work toward optimizing the delivery of gene-based MCMs for increased efficacy and tolerability. Other government agencies – including the DoD’s Joint Program Executive Office for Chemical, Biologic, Radiological, and Nuclear Defense (JPEO-CBRND), the Biomedical Advanced Research and Development Authority (BARDA), and the National Institute of Allergy and Infectious Disease (NIAID) – also have recognized the power of gene-encoded antibody technology to fight a range of biothreats and infectious diseases.

Progress in the ADEPT program has earned supplemental 6.2 funding from the U. S. Congress in response to the 2014 Ebola virus outbreak in West Africa. To address current and future Ebola outbreaks, these funds were directed toward development, manufacture, and/or clinical evaluation of several MCMs, including one based on a monoclonal antibody referred to as mAb-114, which was previously discovered by scientists at NIAID’s Vaccine Research Center. This therapeutic antibody was authorized for emergency use (EUA) in the 2017 Ebola outbreak in the Democratic Republic of Congo, where it conferred significant survival benefits over other EUA-sanctioned Ebola therapeutics. To enable continued availability of mAb-114, DARPA and JPEO-CBRND in 2018 co-funded the manufacture of additional doses at Ology Biosciences through its DoD-funded Advanced Development and Manufacturing (ADM) facility.

ADEPT investments also were foundational to an ambitious follow-on DARPA program, the Pandemic Prevention Platform (P3). Its goal is to prevent pandemic outbreaks by creating a platform capable of identifying, testing, and mass-producing MCMs within 60 days of the detection of an outbreak. The emergence of COVID-19 in late 2019 and its pandemic spread in 2020 reinforced the importance of ADEPT and P3 in the most forceful of terms possible. P3 is part of a yet more comprehensive portfolio of DARPA programs that stand a chance of ultimately delivering a technology framework that could quash just about any outbreak of a known or emerging infectious disease before it could grow into a pandemic.

DARPA pioneered the original concept of MCMs based on the encoding of antibodies in RNA and DNA. The agency helped usher the technology from the laboratory to clinical testing and to the verge of clinical practice in 2020. With ADEPT, P3, and related programs, DARPA seeks nothing less than to deliver the knowledge and know-how needed to protect U.S. warfighters and the general citizenry from threats posed by any dangerous pathogen, whether previously encountered or new to humankind.

• NOTE: 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 with a range of technologies and practices marked by early detection of an outbreak and, within 60 days, development and widescale deployment of protective countermeasure 

"[...]   In 2012 with the ADEPT:PROTECT program*, DARPA began investing in the development of gene-encoded vaccines, a new category of preventive measures based on DNA or RNA. In this approach, genes that encode immunestimulating antigens, such as the spike proteins on the surfaces of viruses like the one (SARS-CoV-2) that causes COVID-19, are delivered directly to a recipient’s body. There, the instructions carried in the DNA or RNA elicit the body’s own cells to manufacture the antigenic viral protein, which, in turn, elicits an immune response to the virus.

Gene-based vaccines have shown great promise as a means to provide safe, reproducible, long-term immune protection. For vaccines to work, however, they often require more than one dose and it often takes weeks to months before a recipient’s immune system builds up sufficient protection again the vaccine’s viral target. With these biomedical realities come threats to warfighters if they deploy to pathogen-rife regions before having established relevant immunity and threats to military missions due to delayed deployment of personnel until they achieve immune protection.   [...]"

• Title: Autonomous Diagnostics to Enable Prevention and Therapeutics (ADEPT)

• Description: The Autonomous Diagnostics to Enable Prevention and Therapeutics (ADEPT) program will develop the underlying technologies to rapidly respond to a disease or threat and improve individual readiness and total force health protection by providing capabilities which are currently available only in centralized laboratories in the U.S. to non-tertiary care and individual settings. ADEPT will develop and exploit synthetic biology for the in vivo creation of nucleic acid circuits that continuously and autonomously sense and respond to changes in physiologic state and for novel methods to target delivery, enhance immunogenicity, or control activity of vaccines, potentially eliminating the time to manufacture a vaccine ex vivo. ADEPT advancements to control cellular machinery include research to optimize orthogonality and modularity of genetic control elements; identify methods to increase sensitivity and specificity; and demonstrate methods to control cellular machinery in response to changes in physiological status. ADEPT will develop methodologies for measuring health-specific biomarkers from a collected biospecimen to enable diagnostics at the point-of-need or resource limited clinical facilities (point-of-care), in-garrison or deployed. Additionally, ADEPT will develop techniques that will enable the rapid establishment of transient immunity through stimulation of the production of components of the immune system to impart effective but temporary protection. This transient immunity would bridge the time gap between the delivery of a vaccine and the development of a long term protective immune response. Applied research efforts are budgeted in PE 0602115E, Project BT-01.

• FY 2013 Accomplishments:

  • • Demonstrated development of modular and orthogonal nucleic acid-based elements for application within a sense-and-respond circuit that operates within the context of a mammalian cell.

    • Demonstrated controlled expression in mammalian cells of synthetic circuit that responds to physiological biomarkers associated with health status.

    • Quantified sensitivity and specificity of developed molecular approaches designed for deployable diagnostics using physiological concentrations of clinically relevant analytes in complex biospecimens.

    • Quantified performance of biostabilization reagents/materials demonstrating analytical recovery of clinically relevant molecules equivalent to traditional stabilization methods that require cold-chain storage.

    • Quantified performance of methods for room temperature analyses and reagent stabilization demonstrating analytical results with similar-to-enhanced performance as compared to current laboratory methods for clinical diagnostics.

    • Quantified detection limits achieved with signal amplification methods, demonstrating performance superior to current state of the art methods for quantification of low abundance biomarkers in an actionable timeframe.

    • Developed new sample preparation methods suitable for simple and multiplexed analysis of biospecimens that are either selfcollected under low-resource settings or collected by trained professionals at the physician-office settings.

    • Determined materials properties and fluidic control requirements for integration of diagnostic methodologies.

    • Quantified the level of antibody and immunoadhesin production directed by the administration of synthetic oligonucleotides in comparison to standard vaccine delivery.

    • Investigated the impact of the Ribonucleic Acid (RNA) sequence on the therapeutic strength of immune response in vivo.

• FY 2014 Plans:

  • • Demonstrate in mammalian cells the function of a synthetic circuit that can integrate multiple signals associated with health status and respond with a targeted change in cell function.

    • Demonstrate the ability to generate synthetic nucleic acid and protein circuit components that respond to an exogenously supplied small molecule drug trigger.

    • Demonstrate biostabilization reagents/materials with biospecimen types and physical formats appropriate for integration into devices for collection and transport of patient samples for diagnostic analysis, and integration into on-person diagnostic devices.

    • Demonstrate signal amplification methods in conjunction with processing/assay methods.

    • Optimize developed sample preparation methods and test efficacy using biospecimens representative of those either self-collected under low-resource settings or collected by trained professionals at the physician-office settings to assist the diagnosis of an individual.

    • Develop advanced materials for incorporation in disposable diagnostic devices.

    • Optimize advanced microfluidic methods for no/low power flow control.

    • Demonstrate delivery of synthetic oligonucleotide constructs to cells appropriate to produce an antibody response.

    • Demonstrate antibody and immunoadhesin production targeted to specific disease classes.

    • Optimize antibody sequence for maximal therapeutic strength of immune response in vivo.

• FY 2015 Plans:

  • • Demonstrate ability to administer nucleic acid encoding multiple antibodies to protect against existing, unmet, clinical targets; emerging global infectious diseases; and known, engineered biothreats.

    • Demonstrate onset of protection within hours after delivery and duration of therapeutic response greater than IV administered antibodies.

    • Demonstrate optimized, high sensitivity assay methods for protein and nucleic acid biomarkers, suitable for incorporation in deployable devices.

    • Demonstrate advanced materials properties and incorporation of developed materials into disposable assay formats.

    • Demonstrate advanced methods for reagent stabilization and delivery for assays developed for deployable devices.

    • Demonstrate sample preparation methods in conjunction with developed assays and quantify performance metrics.

    • Demonstrate performance of developed assays using advance no/low power microfluidic methods.

    • Measure performance of developed diagnostic methods and demonstrate capability to measure clinically relevant analyte levels in appropriate biospecimen matrices.

    • Demonstrate in mammalian cells the function of a synthetic circuit that can control the timing and level of expression of a protein when expressed from an RNA-based expression vector.

    • Demonstrate in mammalian cells the function of a synthetic circuit that can integrate at least two physiological signals associated with a change in health status and respond to at least two exogenously added small molecules, and respond with a targeted change in cell state.

    • Demonstrate the ability to generate a synthetic antibody via continuous evolution that can specifically bind to a defined target in mammalian cells.

"[AbCellera Biologics Inc.], of Vancouver, British Columbia, said it completed its first antibody discovery partnership with Massbiologics of the University of Massachusetts Medical School, funded by the Defense Advanced Research Project Agency under the ADEPT-PROTECT program [See ADEPT program (DARPA)  ] and directed toward rapid human antibody discovery for infectious diseases. Screening of more than 10 million single B cells discovered a panel of hundreds of ultra-rare antibodies against multiple targets from enterotoxigenic Escherichia coli. In a separate element of the collaboration, Abcellera also identified hundreds of human anti-Ebola antibodies from a single blood sample obtained from a convalescent human patient, and provided sequences of a select subset of antibodies in less than a week.  "

Subtitle : New collaboration targeting hospital-acquired infections follows on [AbCellera Biologics Inc.]’s success in two previous DARPA-funded collaborations with MassBiologics.

Vancouver, Canada (July 20, 2016) – [AbCellera Biologics Inc.], a biotechnology company specializing in the rapid discovery of monoclonal antibodies from natural immune cells, today announced its third antibody discovery collaboration with MassBiologics of the University of Massachusetts Medical School.

This pathogen is among the leading causes of hospital-acquired (nosocomial) infections worldwide, and has emerged as a major concern for patients

This new collaboration, funded by the Defense Advanced Research Project Agency (DARPA) under the ADEPT-PROTECT program [see ADEPT program (DARPA)], focuses on addressing the rapidly-growing, unmet global health threat caused by the multidrug resistant bacteria, Klebsiella pneumoniae. This pathogen is among the leading causes of hospital-acquired (nosocomial) infections worldwide, and has emerged as a major concern for patients. [AbCellera Biologics Inc.] will apply its single-cell antibody discovery platform to identify panels of antibody candidates against Klebsiella pneumoniae directly from human volunteers.

“AbCellera’s technology has the throughput, speed and capacity to deeply screen natural human antibody responses to these pathogens,” said Carl Hansen, CEO and co-founder of AbCellera. “We are pleased at the opportunity to expand our collaboration with MassBiologics, and believe this work will further demonstrate the strength of our approach for rapid human antibody discovery, immune profiling, and vaccine development.” This partnership builds on the successes of two earlier DARPA-funded collaborations between AbCellera and MassBiologics, from which novel antibodies for potential therapeutics to enterotoxigenic E. coli and Ebola virus were discovered.

• About AbCellera Biologics Inc. :   AbCellera is a privately held biotechnology company that provides enabling technologies for the discovery and development of monoclonal antibody (mAb) therapies directly from natural immune cells. AbCellera’s lead technology is a proprietary single cell antibody discovery platform that provides pharma and biotech partners with the ability to rapidly identify mAb therapeutic candidates from the natural immune repertoires of any species, including humans.
• About MassBiologics  :   MassBiologics of the University of Massachusetts Medical School is the only publicly owned, non-profit FDA-licensed manufacturer of vaccines and other biologic products in the United States. The laboratory was established in 1894 by the state Board of Health to produce diphtheria antitoxin. Since that time, the focus at MassBiologics has been to improve public health through applied research, development and production of biologic products. In 1997, the Commonwealth of Massachusetts transferred MassBiologics operations from the Department of Public Health to UMass Medical School to “maintain their public purpose, preserving their ability to compete in an increasingly competitive marketplace and to maximize their value to the Commonwealth.”

The increasing threat of infectious diseases is intensifying the need for breakthrough technologies and capabilities to protect first responders and equip them with therapeutics that can halt the impact of infectious agents. Current approaches for recent public health emergencies due to infectious diseases have not produced effective preventive or therapeutic solutions in a relevant timescale. Examples from recent outbreaks such as H3N2 (flu), Ebola, and Zika viruses highlight the significant lag in deployment and efficacy of life-saving solutions.

To address the growing threat from infectious diseases as well as to properly equip DoD Service members who regularly deploy worldwide to provide assistance in all manner of high-risk environments, DARPA launched the Pandemic Prevention Platform program (P3). The P3 program, which began in 2017, seeks to halt the spread of any infectious disease outbreak before it can escalate into a pandemic. This last weekend, at the AAAS Annual Meeting in Austin, Texas, Col. Matthew Hepburn, M.D., the program manager for P3, announced that all performer institutions are now on contract and moving forward with the program’s goals of developing technology to halt the spread of pandemic infectious diseases. The institutions funded through the P3 program include Duke University, Vanderbilt University, MedImmune, and Abcellera Biologics Inc.

Under the program, P3 performer teams are developing technologies for an end-to-end pandemic response platform that includes the ability to study viruses for downstream antibody discovery and final evaluation and testing of candidate therapeutic products. Teams will demonstrate the ability to rapidly discover and optimize antibodies so that they are most effective against an infectious agent. Further, the P3 teams are tasked with developing technologies to deliver antibodies using nucleic acid technology, and achieve sufficient serum concentrations of the antibodies for protection against the pathogen within three days after administration.

The nucleic-acid-based technologies that are central to P3 research, particularly those focused on DNA and RNA, include some developed under DARPA’s Autonomous Diagnostics to Enable Prevention and Therapeutics (ADEPT) program. Through these tools, researchers can identify protective antibodies from recovering patients and then manufacture genetic constructs capable of instructing a patient’s body to produce similar protective antibodies. Significant quantities of these nucleic acid “blueprints” can be rapidly manufactured compared to existing antibody production methods.

“Advances in medical countermeasures have formed a strong foundation, enabling the creation of a true end-to-end pandemic prevention platform. However, experience gained from conventional responses to emerging infectious diseases has demonstrated that significant bottlenecks hinder the rapid response to an emerging infectious threat,” said Hepburn. “P3 seeks to demonstrate an ability to rapidly produce virus needed to test and evaluate therapies, obtain high potency antibodies within the first weeks of an outbreak, and to scale delivery methods into humans to produce protective levels inside the patient.”

According to Hepburn, P3 performers are expected to demonstrate safety of their nucleic acid product against one target pathogen in a phase I clinical trial. Ultimately, the performer teams will be evaluated on the results of their clinical trial and their ability to complete the end-to-end process within 60 days from the time the pathogen-containing sample is first obtained. Also, to demonstrate the broad utility of the platform, each team will target a variety of viral pathogens including influenza, chikungunya, MERS-CoV, and Mayaro virus, among others.

For more information on the P3 program, please visit: http://www.darpa.mil/program/pandemic-prevention-platform.

Also, to hear Dr. Hepburn talk about P3 as well as the rest of his research portfolio at DARPA, listen to him on the just-released Voices from DARPA Podcast episode, The Disease Slayer: http://www.darpa.mil/about-us/podcast.

 Under DARPA’s Pandemic Prevention Platform (P3) program, [AbCellera Biologics Inc.] will apply its state-of-the art capabilities in human antibody discovery and immune profiling to establish rapid countermeasures for viral pandemics.

Vancouver, Canada (March 13, 2018) - [AbCellera Biologics Inc.] announced today that it was awarded a contract from the Defense Advanced Research Projects Agency (DARPA) to develop rapid countermeasures against viral outbreaks. Over the four-year contract, AbCellera will receive up to USD $30 million in funding to establish an end-to-end platform for rapid pandemic response, and will lead an internationally recognized team of experts in virology, antibody discovery, and gene therapy.

The project is part of the Pandemic Prevention Platform (P3), a high-priority initiative of DARPA’s Biological Technology Office. The P3 program seeks to develop a robust technology platform for pandemic response capable of developing field-ready medical countermeasures within 60 days of isolation of a viral pathogen. To achieve this ambitious goal, AbCellera and its partners will develop and integrate innovative technologies for viral culture and production, rapid human antibody discovery, protein engineering, and delivery of nucleic acid-encoded antibodies as prophylactic protection against viral infection. [AbCellera Biologics Inc.]'s platform development and testing will include the discovery of thousands of human antibodies against a wide array of influenza strains and validation using a variety of other high-priority viral pathogens. In addition to the proposal submitted by the AbCellera-led team, the P3 program has funded three other consortia led by Medimmune, the Duke Human Vaccine Institute, and Vanderbilt University Medical Center.

Carl Hansen, founding CEO of [AbCellera Biologics Inc.], commented: “Through the P3 program, DARPA has set a bold vision to establish effective response capabilities for viral threats. The recent Ebola and Zika pandemics have made it clear that we are not equipped to deal with viral pandemics. The severity of seasonal flu this year is a sobering reminder that viral outbreaks present a serious risk to public health for which we must be better prepared. We are honoured to lead a team to help achieve the important goals of the P3 program.”

Col. Matthew Hepburn, the DARPA P3 Program Manager, noted in DARPA’s original announcement of the program: “We need to be able to move at this speed considering how quickly viral outbreaks can get out of control. The technology needs to work on any viral disease, whether it’s one humans have faced before or not. If we’re successful, DARPA could take viral infectious disease outbreaks off the table.” [...]

An announcement of the P3 program was made earlier by DARPA: http://www.darpa.mil/news-events/2018-02-22

• About AbCellera Biologics Inc. :   AbCellera is a privately held company that engages in partnerships to discover and develop next-generation therapeutic antibodies. AbCellera’s single-cell platform integrates end-to-end capabilities for therapeutic antibody discovery through a combination of technologies including proprietary immunizations, microfluidics, high-throughput imaging, genomics, computation, and laboratory automation. Ultra-deep screening of single B cells allows unprecedented access to natural immune responses, enabling rapid isolation of large and diverse panels of high-quality lead antibodies from any species, including humans.

SOMETIME IN THE next day or two, a medical courier will deliver a styrofoam cooler to the offices of [AbCellera Biologics Inc.], a biotech firm headquartered in downtown Vancouver, British Columbia. Inside the box, packed in dry ice, will be a vial of blood prepared by researchers at the US National Institutes of Health, who drew it from a patient infected with the Covid-19 coronavirus.

The blood sample will be taken to AbCellera’s laboratory and placed in a microfluidic chip the size of a credit card that will isolate millions of white blood cells and put each one into a tiny chamber. Then the device will record images of each cell every hour, searching for the antibodies each one produces to fight the coronavirus.

“We can check every single cell within hours that it comes out of the patient,” says [AbCellera Biologics Inc.]’s CEO, Carl Hansen. “Now with a single patient sample we can generate 400 antibodies in a single day of screening.”

Antibodies are proteins that the immune system creates to remove viruses and other foreign objects from the body. Vaccines work by stimulating the body’s own immune system to produce antibodies against an invading virus. This immunity remains, should the virus attack again in the future. Vaccines provide protection for years, but they also take a long time to develop. Currently, there is no vaccine that can be used against the virus that causes Covid-19, although drug companies like Johnson & Johnson and Cambridge-based Moderna are working on developing them. So researchers are instead investigating whether an infusion of antibodies alone can be used as a short-lived—but immediately available—treatment to protect doctors and hospital workers, as well as family members of infected patients who need it right away.

The Pentagon’s Defense Advanced Research Projects Agency, or Darpa, launched its Pandemic Prevention Platform program two years ago with the goal of isolating and reproducing antibodies to deadly new viruses within 60 days. It enlisted researchers at Duke and Vanderbilt medical schools, as well as [AbCellera Biologics Inc.] and pharmaceutical giant AstraZeneca.

In preparation for an outbreak like the coronavirus now gripping China, scientists with the program made test runs using viruses responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Both are members of the coronavirus family and closely related to Covid-19.

After isolating these antibodies, the researchers then capture their genetic code, using it as a blueprint to mass produce them. Their goal is to create an antibody treatment that can be injected directly into a patient, giving them an instant boost against the invading coronavirus.

“We are going to take the patient’s blood, identify the antibodies, and do it very rapidly,” said [Dr. Amy Lynn (Haas) Jenkins (born 1979)], program manager at Darpa’s biological technologies office, which is supporting [AbCellera Biologics Inc.]’s work with a four-year, $35 million grant. “Once we have the antibodies isolated, then we can give them back to people who are not yet sick. It’s similar to a vaccine and will prevent infection. The difference is that vaccines will last a long time. Our approach is immediate immunity and doesn’t last as long.”

If all goes well, [Dr. Amy Lynn (Haas) Jenkins (born 1979)] said, the antibody countermeasure would last several months rather than the several years that vaccines are effective. That said, the researchers still need to test the safety and efficacy of this antibody protein in animal and human clinical trials.

Of course, developing a treatment using antibodies isn’t simple. First, only one of the 15 US patients struck by Covid-19 has so far agreed to donate blood. (China has thousands of infected patients, but US researchers haven’t been able to get their blood for research here.) That means that [AbCellera Biologics Inc.] is on the waiting list to get a few drops of that valuable sample, along with several other companies and academic institutions that are partnering with Darpa and the CDC to develop treatments. “We have mobilized our team and are getting in place as soon as it arrives,” says Ester Falconer, AbCellera’s head of research and development. “We are raring to go.”

A team of Chinese scientists announced on January 31 that they had found an antibody which binds to the surface of the coronavirus and appears to neutralize it. Their research paper, which appeared as a preprint on the site BioXArchiv, hasn’t been peer reviewed by other scientists. And it is not clear how effective the antibody would be once it is mass produced and then tested in animals or humans.

Should antibody treatments work, there’s also the question of who would get them first, whether its first-line responders in specific hospitals where Covid-19 patients are being treated, or perhaps people at home with family members who test positive. (The antibody supply will likely be distributed by federal public health officials.)

Another potential looming issue is a bottleneck for scaling up antibody mass production. Medical experts say it's unlikely that pharmaceutical makers can make enough to protect everyone who needs them. “The constraint is production capacity,” says [Dr. James Vincent Lawler (born 1969)], an emerging disease specialist at the University of Nebraska Medical Center who is not involved in the Darpa program. “We are getting pretty good at finding appropriate antibody preparations. But the problem we still have is: How do we produce those rapidly enough to have an impact in a global epidemic?”

To protect the doctors, nurses, and health care workers at the more than 5,500 hospitals and medical centers in the US would take more than 1 million doses of treatment, according to [Dr. James Vincent Lawler (born 1969)]. “Scaling to a million doses of antibody product is a heavy lift to do in a few months,” he says. “We don’t have scaling capacity for therapeutics or prophylaxis in that time frame. In two years, we could get to that point.”

Despite those obstacles, medical researchers involved in the Darpa program say they are ready to fire up sophisticated tools for cellular screening and imaging that have been boosted in recent years by advances in machine learning and pattern recognition. [AbCellera Biologics Inc.]’s machine is trained to look through millions of images to find the perfect one of an antibody binding to the surface of the virus.

At Vanderbilt University’s School of Medicine, Robert Carnahan is also waiting for the blood from that first US patient sample to run through Vanderbilt’s own antibody screening technology. Carnahan and his colleagues at the Vanderbilt Vaccine Center used their method last year to find new antibodies against the Zika virus. Their initial test resulted in 800 antibodies that were narrowed down to 20 for animal testing, and finally one that stopped the virus from spreading. That entire process only took 78 days, Carnahan said.

“We need the most potent antibodies,” Carnahan said. “That requires a lot of work. Most of the work in our lab during the Zika trial was to take a small subset into these more detailed studies. In the midst of a pandemic, you don’t have that luxury.”

Carnahan said he expects to receive the US coronavirus blood sample any day now. Given the lack of US patients, his colleagues are also trying to get them from infected patients living outside of China. But acquiring the samples requires working directly with hospital administrators and public health officials in each country, because no international body is yet coordinating a sharing program.

“Everyone’s anxious,” Carnahan said about the researchers on his team at Vanderbilt. “When the human samples become available, things will progress quickly. And it’s probably OK from a safety perspective that these samples aren’t flying all around the country.”

The scientists were working through the night over a weekend in February in their Vancouver offices, running a blood sample from an early American covid-19 survivor through a credit card-sized device made up of 200,000 tiny chambers, hoping to help save the world.

Their mission was part of a program under the Pentagon’s secretive technology research agency. The goal: to find a way to produce antibodies for any virus in the world within 60 days of collecting a blood sample from a survivor.

Established years before the current pandemic, the program was halfway done when the first case of the novel coronavirus arrived in the United States early this year. But everyone involved in the effort by the Defense Advanced Research Projects Agency (DARPA) knew their time had come ahead of schedule.

The four teams participating in the program abandoned their plans and began sprinting, separately, toward the development of an antibody for covid-19, the disease caused by the coronavirus.

“We have been thinking about and preparing for this for a long time, and it’s almost a bit surreal,” said Amy Jenkins, manager of DARPA’s antibody program, which is known as the Pandemic Prevention Platform, or P3. “We are very hopeful that we will at least be able to have an impact on this outbreak. We want to make a difference.”

In that program and others, DARPA has quietly been seeding the ground for the United States to produce a rapid cure for a pathogen like covid-19 for years.

The U.S. government’s response to the pandemic has been impugned as slow and haphazard, with flawed test kits, limited contact tracing, insufficient protective gear, late encouragement of masks and at times baffling messages from President Trump.

But DARPA’s story is a counterexample of U.S. government foresight, one that began more than a decade ago with the aim of finding super-fast ways to protect American troops if they were to confront a deadly new virus in the field.

If it weren’t for DARPA’s investments over the past decade and earlier, largely outside the glare of Washington’s partisan politics, the American race toward a vaccine and antibody therapy to stop the coronavirus most likely wouldn’t be moving as quickly as it is today.

“Being at DARPA at this time ... is exciting in some ways because we get to see the research work that was funded that was done ten to fifteen years ago now really starting to pay off,” acting director Peter Highnam said in a discussion with reporters on Thursday.

The first company in the United States to enter clinical trials with a vaccine for the virus was funded by DARPA. So was the second company. And the P3 program has already led to the world’s first studyin humans of a potential covid-19 antibody treatment. If successful, antibody treatments would offer up to three months of immunity against covid-19. Unlike vaccines, they could also help heal people already infected with the virus.

Some of the vaccines and antibodies linked to DARPA could be ready later this year, which would mark one of the speediest responses to a global pandemic in the history of medicine. Experts say it normally takes four to 10 years to devise, test and produce a vaccine for a new pathogen. Antibodies, which the body creates to combat a virus, have taken years to discover, let alone produce.

DARPA is far from exclusively responsible for the fast pace. Other countries, including China, where the virus originated, are also moving quickly toward a cure. So are firms unaffiliated with DARPA.

Still, the Pentagon agency played a significant role in advancing the science that is making the quick pace possible and setting a North Star for researchers.

“I think their role is very important,” said [Dr. James Earl Crowe Jr. (born 1961)], director of the vaccine center at Vanderbilt University, one of the four participants in the P3 program. “The reason is they have catalyzed more rapid progression than otherwise would have happened. And the reason they accomplished it was they were willing to state . . . grand challenges.”

[Dr. James Earl Crowe Jr. (born 1961)] said he and his colleagues laughed when DARPA put out its request in 2017 for a system that could produce a human-ready antibody from a convalescent blood sample in 60 days.

“Somehow, in setting that aspirational goal, after the first brainstem reaction of, ‘That’s ridiculous,’ the next step is, ‘Well, how close could we get?’ ” Crowe said. “Then, you start buying in to the belief that it could be possible.”

'Ringing people's doorbells'

Established in 1958 in response to the Soviet Union’s launch of Sputnik, DARPA was created by President Dwight D. Eisenhower out of a sense of urgency.

Washington could have sent the first satellite to space, but Moscow got there first — and it wasn’t because the United States lacked the science. The American government simply didn’t move fast enough.

DARPA was the answer to that problem.

The nimble military science research agency wouldn’t invent things itself. Rather, its officials would look across the American scientific landscape — to universities, military labs and defense contractors — and channel emerging technologies into risky mega-endeavors to prevent another Sputnik. The agency’s pie-in-the-sky projects would have a high risk of failure, but if successful, would transform the U.S. military and possibly society, too.

Over the years, DARPA-funded projects have created the building blocks of GPS, the first computer mouse and the protocols that underpin the modern Internet. The agency pioneered stealth technology that made American fighter jets all but invisible to enemy radar. And it advanced a bevy of new weaponry, including drones.

In the years after the attacks of Sept. 11, 2001, a series of anthrax incidents, combined with overseas intelligence about potential biological threats, heightened fears of bioterrorism and drove DARPA to invest in faster ways to respond, including technology to accelerate vaccine development, spot emerging viruses and speed up pharmaceutical manufacturing.

A decade ago, a brainy Air Force doctor named Dan Wattendorf helped push rapid pandemic response further to the top of DARPA’s priority list.

[See https://www.youtube.com/watch?v=UD-ex1nrtGI .. Dan Wattendorf: Outpacing Infectious Disease (DARPA "Wait, What?") .. 2015 ]

[See https://www.gatesfoundation.org/about/leadership/dan-wattendorf ] 

[ https://www.youtube.com/watch?v=dYEbvsx6Q_I ] 

Regularly citing the 1918 flu pandemic, the DARPA program manager saw how a novel pathogen, whether from another species or an enemy’s lab, could cripple the American military in the field.

“If we need to deploy someone in harm’s way and it’s a new virus, you don’t have time to wait for a new vaccine,” Wattendorf said. “That could be a decade.”

Wattendorf had ideas for a solution. In 2010, he took to a conference room at DARPA headquarters in Northern Virginia with notes scribbled on his hand to make a pitch.

At the time, the Obama administration was emphasizing the need to step up pandemic response capabilities in the wake of the H1N1 outbreak, and DARPA was increasingly focusing on biology — an emphasis that would lead to the agency’s first biotechnology office in 2014.

In the conference room, Wattendorf outlined his ideas to agency higher-ups. Regina E. Dugan, the DARPA director at the time, ribbed him for the writing on his hand before greenlighting his proposal.

The result was a program called ADEPT, which invested $291 million from 2011 to 2019 in an array of technologies — including a credit card-sized device for rapid antibody discovery developed by the Vancouver-based firm AbCellera — that, taken together, could significantly reduce the timelines for vaccines and antibodies.

“It may turn out to be the most important program from my time at the agency,” said Dugan, who ran DARPA from 2009 to 2012.

Chief among Wattendorf’s targets for the program: delivering vaccines and antibodies by implanting their genetic code.

Traditional vaccines inject what’s known as an antigen — usually a piece of live or deactivated virus that is sufficient to provoke the immune system into a protective response. Antigens are typically manufactured in a long process that involves growing live virus in chicken eggs in bioreactors.

Wattendorf hoped to short-circuit it. He wanted to inject genetic code that would prompt the human body to create the antigen in its own cells, cutting out the manufacturing process. The immune system would recognize the antigen in the cells and launch a protective response.

By 2010, scientists had tested the idea using DNA with mixed results. Wattendorf wanted to try its single-stranded sibling RNA.

If successful, RNA could be used to develop both vaccines and antibodies, shortening development timelines from years to days before clinical trials, he thought. It also offered a one-size-fits-all approach; in the future, scientists would need only the genetic code of a virus to create a vaccine.

At the time, many considered it a fool’s errand. Being so ephemeral, RNA is unstable in the environment and highly susceptible to degradation. It was unclear how to get it into a human cell. Over at the National Institutes of Health, where Wattendorf previously worked, research into DNA vaccines was presenting enough hurdles. Few wanted to take the risk of trying RNA, too.

“Skeptics cited the lack of evidence that it would work, and Dan cited the lack of evidence that it wouldn’t,” Dugan recalled. “That’s very typical of a DARPA program.”

By 2019, a project DARPA funded at the Massachusetts-based company Moderna demonstrated in a Phase 1 clinical trial that RNA could indeed deliver an antibody to humans and provide protection against the mosquito-borne virus chikungunya. It was an affirmation of Wattendorf’s bet that came after years of DARPA funding the effort.

Today, RNA vaccines, although still experimental, are among the fastest-moving candidates in the race to stop covid-19. In March, Moderna was the first company in the United States to enter Phase 1 trials with a covid-1 vaccine using RNA. The company injected its first test into a human 66 days after receiving the virus’s genetic code. Phase 2 trials began in May, and Phase 3 began on July 27, making it possible that the vaccine could be available by the end of the year.

In addition to Moderna, two other pharmaceutical companies — Pfizer and CureVac — are pursuing RNA vaccines, as is a small laboratory at Imperial College in London and the People’s Liberation Army Academy of Military Sciences in China. CureVac was also funded by DARPA.

“Is an RNA vaccine going to potentially be made available at scale?” Wattendorf said. “We are seeing very well that could happen. It demonstrates the role DARPA can play in creating these capabilities.”

Wattendorf also continued DARPA investments in vaccines delivered using DNA.

[Inovio Pharmaceuticals, Incorporated], funded by DARPA, entered Phase 1 trials for its DNA-delivered covid-19 vaccine in April, making it the second company to enter trials in the United States. The Pennsylvania-based firm, which began trials 80 days after receiving the virus’s genetic code, is looking to begin its Phase 2 and 3 trials this summer, pending regulatory approval.

DARPA also funded other technologies for rapid vaccine development, including companies that manufacture vaccines by growing proteins in tobacco-like plants, as well as a “self-assembling vaccine” platform at Massachusetts General Hospital. Mass General’s vaccine center used the platform to develop a more traditional covid-19 vaccine that entered animal testing in early July.

“DARPA comes off as a visionary organization that was ringing people’s doorbells and saying you have to prepare for this,” said Mark C. Poznansky, director of the Mass General Vaccine and Immunotherapy Center. “Some people would say we have enough to worry about without that.”

[Housatonic Note - Mark C. Poznansky is a colleague of Dr. Michael Vincent Callahan (born 1962) ]

'The more aspirational dream'

From the start, Wattendorf and the DARPA team knew that fast vaccines on their own wouldn’t solve the threat that infectious diseases posed to American troops.

It can take weeks for a vaccine to give a person protection, and even then, follow-up booster shots are sometimes needed.

Instead of forcing the body to produce antibodies using a vaccine, why not just inject the best antibody directly? The DARPA team began to pursue that aim in parallel. Wattendorf called the rapid delivery of an antibody using RNA “the more aspirational dream.”

The idea was to take the blood of a virus survivor and quickly identify the best antibody out of thousands in the bloodstream. Then, the genetic code of that antibody could be injected into troops to give them temporary protection against the virus immediately. Protection could range from a few weeks to a few months — enough time for a deployment.

In a pandemic, DARPA envisioned using such antibodies as a “firebreak” — an obstacle that slows the rapid spread of a conflagration.

For example, if one person in a nursing home tests positive, the antibody could be given to all the other residents to prevent the spread of the illness.

Critically, unlike vaccines, antibodies can also treat those who have already fallen ill.

DARPA had funded the development of rapid antibody technologies for years. Then, around 2016, DARPA Director Arati Prabhakar wanted to weave them together into a production line and test it.

“Very few interesting problems just have a miracle, single-threaded solution,” Prabhakar said.

The result was the Pandemic Prevention Platform, which Prabhakar signed off on before leaving DARPA in January 2017. The goal of the four-year $96 million program was to develop an antibody for any virus within 60 days of receiving the blood sample of a survivor.

When covid-19 arrived in the United States, the program’s participants — AbCellera, Vanderbilt University, Duke University and AstraZeneca — had already done test runs with various viruses to see where they could cut time on their quest to hit the 60-day goal.

As they pivoted to tackle covid-19, Jenkins, the DARPA program manager, knew the participants wouldn’t meet the 60-day timeline but thought some could come close to 90 days, and potentially help end the global pandemic.

Some of the participants obtained a blood sample in February from one of the first American covid-19 patients to return from China. But the sample wasn’t great; the patient had recovered fairly recently and therefore didn’t have a sufficiently mature immune response from which to draw good antibodies.

At AbCellera, chief executive Carl Hansen forged ahead with the sample anyway.

On Feb. 28, AbCellera’s employees began working round-the-clock over a weekend in their Vancouver offices, ultimately finding 550 unique antibodies using their tiny device.

Hansen contacted the pharmaceutical company Eli Lilly and came to an agreement, announced March 13, whereby Lilly would manufacture the best antibody and take it into clinical trials.

But first they had to decide which antibody was the winner.

Daniel Skovronsky, Lilly’s chief scientific officer, said the pharmaceutical company threw the normal years-long process out the window and immediately began scaling up to make the top 100 antibodies to save time, even though only one would proceed.

The company worked with AbCellera, the National Institute of Allergy and Infectious Diseases, and academic researchers to conduct experiments on the antibody candidates. By late April, they had to pick which, if any, should proceed to the last and most expensive stage of scale-up.

The best candidate, they determined, was antibody No. 555.

“This was a tough decision,” Skovronsky said. “There were mixed views.”

The first patient was dosed on May 29, 91 days after AbCellera received the blood sample. It became the world’s first study of a potential covid-19 antibody treatment in humans, according to Lilly. The national registry of clinical trials indicates that Phase 2 is expected to be completed in August.

At Vanderbilt, [Dr. James Earl Crowe Jr. (born 1961)] wanted a better sample than the initial one obtained in February. By mid-March, his team found two people in the United States who had been infected 50 days earlier in China.

After screening the samples, his team narrowed their list to the 30 best antibodies and then interacted with companies interested in producing them.

IDBiologics Inc., a Nashville-based biotechnology start-up that Crowe co-founded, will begin human trials with one of the antibodies in August, he said, with possible availability in the United States under emergency use early next year if all goes well.

After licensing six antibodies from Vanderbilt and screening their own in house, AstraZeneca picked two antibodies to take into clinical trials this summer as a pair, said Mene Pangalos, executive vice president for biopharmaceutical research and development.

The global pharmaceutical industry can produce billions of vaccine doses, but it lacks the capacity to manufacture antibodies at such a large scale. At least initially, the antibodies won’t be delivered using RNA, although Duke University plans to manufacture an RNA version of its antibody, meeting the original DARPA vision for the program.

Wattendorf, who has left DARPA and now works at the Bill and Melinda Gates Foundation, said that looking back 10 years, the agency was trying to solve the problem of speed to protect American forces.

“These things were funded to be fast,” Wattendorf said. “They were not actually funded to be global scale.”

Other DARPA efforts did take aim at the scale question. The agency, for example, funded technology to produce vaccines using plants instead of chicken eggs — an approach that has the benefit of easy mass scale-up. One of the firms DARPA funded, Quebec City-based Medicago, began Phase 1 clinical trials in mid July with a covid-19 vaccine produced in a tobacco-like plant and plans to enter Phase 2 and 3 trials in October.

Mass production and its costs are now a problem that governments the world over are looking to solve, all while watching the results of the fastest-moving clinical trials.

“While we’re all hoping our therapies work, at the end of the day, we all hope somebody’s therapy works,” Pangalos said. “Because we all want to get back to some semblance of reality.”