DARPA’s gambles might have created the best hopes for stopping COVID-19

A U.S. defense agency that specializes in turning science fantasies into realities jump-started technologies and nurtured companies that are now at the forefront of the response to the COVID-19 pandemic.

The Defense Research Advanced Projects Agency (DARPA) has taken risks where others wouldn’t. Its pursuit of high-risk, high-reward technologies, combined with its mission-driven approach to managing projects is promising to pay off in the fight against COVID-19.

DARPA was behind the creation of DNA and RNA vaccines, funding early R&D by Moderna Inc. (NASDAQ:MRNA) and Inovio Pharmaceuticals Inc. (NASDAQ:INO) at a time when the technologies were considered speculative by many scientists and investors.

The military R&D agency believed nucleic acid-base vaccines could be developed much faster than conventional technologies. Its funding, project management and vote of confidence helped de-risk the science and attract investments and partnerships.

NIH selected Moderna as its partner for COVID-19 vaccine development. This week, an RNA vaccine produced by Moderna became the first COVID-19 candidate vaccine to be administered in a Phase I trial.

Inovio is on track to start a Phase I trial of an DNA-based COVID-19 vaccine in early summer.

AbCellera Biologics Inc., one of the first companies out of the starting blocks in the race to discover antibody therapies for COVID-19, is using technology created in response to a DARPA challenge.

Another fast-responder, Vir Biotechnology Inc.(NASDAQ:VIR), is deploying antibody discovery technology that can be traced to a company that received part of its funding from DARPA.

DARPA achieves results by empowering its staff to intensively and flexibly manage projects, awarding milestone-driven contracts rather than grants, and by setting goals that defy conventional wisdom.

While the results of its work are on the frontlines for COVID-19, DARPA continues to set ambitious targets for future outbreaks, including a goal of routinely creating, manufacturing and distributing effective prophylactics within 60 days of a new viral pathogen being identified.

RNA and DNA vaccines

DARPA deserves at least part of the credit for the fact that it’s no longer an extraordinary idea to encode an antigen in DNA or RNA so the human body can create the protein, rather than injecting the antigen as part of a conventional vaccine.

When DARPA began pursuing nucleic acid vaccines in 2011, it was far from clear that they would work.

“It was something that was much too risky for groups like the NIH to fund.”

Amy Jenkins, DARPA

“A lot of people said that would be great if it works, but we don't think it could work, there are too many things that can go wrong,” Amy Jenkins, a program manager in DARPA’s Biological Technologies Office, told BioCentury. She said DARPA scientists concluded “there are scientific reasons why it may not work, but there are also scientific reasons why it may work, and that's absolutely the right place for DARPA to be investing.”

Jenkins highlighted DARPA’s high tolerance for risk. “It was something that was much too risky for groups like the NIH to fund.”

In addition to a high risk tolerance, DARPA operates on a very different model than NIH. Instead of giving multi-year grants that require only periodic progress reports, it awards milestone-based contracts.

DARPA project managers like Jenkins speak with the groups they fund “once a month, sometimes even once every other week, and during something like the coronavirus [outbreak], almost once a day,” she said.

Another difference from NIH is that DARPA is highly focused on achieving its goals, not on advancing science. “We monitor progress closely, but we don't necessarily chase science where it wants to take us. We stay laser-focused on building the capability we need to build. If the path we were taking to getting that capability is not working for scientific reasons, we divert and we take a new path to that same capability.”

CureVac AG became one of the first RNA vaccine companies, in part because of DARPA funding; it was one of the agency’s early bets on the technology. CureVac was also one of the first companies to begin work on a COVID-19 vaccine.

In November 2011, DARPA awarded a $33.1 million contract to a collaboration among CureVac, the Sanofi Pasteur unit of Sanofi (Euronext:SAN; NASDAQ:SNY) and In-Cell-Art S.A.S. to advance CureVac’s RNActive technology platform and evaluate vaccine candidates.

“We don’t necessarily chase science where it wants to take us.”

Amy Jenkins, DARPA

CureVac demonstrated proof-of-principle in a Phase I trial launched in 2013, when its mRNA-based rabies vaccine induced antibodies when delivered with a needle-free device. The study was reported in the Lancet.

CureVac was founded in 2000 and had raised about $84 million at time DARPA selected it to lead the consortium.

DARPA also played an important role in helping Moderna establish its mRNA platform, awarding the biotech a contract for up to $25 million in October 2013. In addition to a vote of confidence for an edgy technology, the DARPA award added non-dilutive funding to the 2012 $40 million venture funding from Flagship Pioneering.

Moderna raised over $600 million in a 2018 IPO and has a market cap of $11.6 billion.

DARPA’s funding was directed towards Moderna’s development of RNA vaccines against the chikungunya and Zika viruses.

Moderna’s Phase I trial of a chikungunya vaccine, completed in September 2019, was an important inflection point for the platform and for RNA vaccine technology. It was, the company reported, the “first systemic mRNA therapeutic to show production of a secreted protein in humans.”

“The researchers have demonstrated that it is feasible to use mRNA sequences to produce and scale a highly potent antibody response against an infectious disease target,” said DARPA’s Jenkins in a statement released in September 2019.

Jenkins added that Moderna’s chikungunya vaccine results were encouraging validation of the “prospects of creating a new, platform-based prophylactic and therapeutic approach that might better protect civilians and service members alike against the relentless threat of pandemic disease.”

In addition to RNA vaccines, DARPA helped advance DNA vaccines from concept to reality.

In 2015, the agency allocated $45 million to a project led by Inovio to develop a vaccine and therapies for Ebola. The program funded development of a DNA-based mAb, a conventional protein-based mAb and a DNA-based vaccine.

In 2019, Inovio announced that in a Phase I trial its DARPA-funded Ebola vaccine candidate produced “100% seroreactivity after two doses and elicited interferon-γ T-cell responses in over 70% of subjects.” Results were reported in the Journal of Infectious Diseases.

Accelerating antibody discovery

Although RNA- and DNA-based vaccines could be a major advance, there are inherent disadvantages for the use of vaccines in general in pandemic response.

“The problem with vaccines is twofold,” DARPA’s Jenkins told BioCentury. “One is that oftentimes if you don't know a lot about your pathogen, so it can take a long time to know which components on the surface of that pathogen would be the right component to inject.”

Even in the case of COVID-19, where the spike protein target was rapidly identified because of prior research on the related coronaviruses SARS and MERS, yielding safe, effective vaccines in less than 12-18 months is not feasible.

The other disadvantage, Jenkins added, is that it can take weeks or months after a vaccine is administered for it to produce immunity. In some cases two or more shots are required.

Antibody-based therapies could offer a faster route -- an option DARPA and companies like Regeneron Pharmaceuticals Inc. (NASDAQ:REGN) and Vir Biotechnology are pursuing.

Unlike vaccines, these mAbs can provide immunity rapidly to yield therapeutic and temporary prophylactic effects.

There is precedent for the use of mAbs to prevent infection. Synagis palivizumab was approved by FDA to prevent serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV.

Two mAbs are being used to treat Ebola patients in the Democratic Republic of Congo: one from Regeneron and another discovered by Humabs BioMed S.A. and developed by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Humabs, which was acquired in 2017 by Vir, was a subcontractor on a DARPA Ebola antibody discovery contract.

One of the past barriers to use of antibodies in pandemics was that it took up to two years to discover an effective antibody.

DARPA, other government and philanthropic funders, and industry have invested in technologies that have cut the time required to screen for and discover antibodies to days.

In 2018, DARPA launched the Pandemic Prevention Platform (P3) that seeks to develop a “scalable, adaptable, rapid response platform capable of producing relevant numbers of doses against any known or previously unknown infectious threat within 60 days of identification of such a threat.”

As part of P3, DARPA awarded a four-year $30 million contract in 2018 to AbCellera to apply its antibody discovery platform to viral pandemics. That’s almost three times the $10.8 million in venture funding AbCellera had raised at that time.

AbCellera, like Regeneron and Vir, initiated an antibody discovery program when the sequence of the virus that causes COVID-19 was announced.

The company received a blood sample from one of the first patients in the U.S. known to have recovered from COVID-19, and within a week identified hundreds of antibodies that could be used to create a product with therapeutic or protective properties.

AbCellera, which is using DARPA funding for its COVID-19 R&D, has signed an agreement with Eli Lilly and Co. (NYSE:LLY) for co-development of an antibody-based product to protect against and/or treat COVID-19. The companies expect to select antibodies, manufacture them, complete preclinical tests and start a Phase I trial within four months (see “AbCellera, Vir Find Partners for COVID-19 mAb Manufacturing Capacity”).

AbCellera also has partnerships with Gilead Sciences Inc. (NASDAQ:GILD), Novartis AG (NYSE:NVS; SIX:NOVN), Sanofi (Euronext:SAN; NASDAQ:SNY), Pfizer Inc. (NYSE:PFE) and Teva Pharmaceutical Industries Ltd. (NYSE:TEVA; Tel Aviv:TEVA), as well as several smaller biotechs.

Ambitious goals for P3

Because of the work it had started under the P3 program, AbCellera was poised to respond to the COVID-19 pandemic.

DARPA, however, has goals that go far beyond rapidly discovering effective antibodies.

“P3 aims specifically to develop a scalable, adaptable, rapid response platform capable of producing relevant numbers of doses against any known or previously unknown infectious threat within 60 days of identification of such a threat,” according to the program’s mission statement.

“I believe that with some more investment in the next two years, we would be close to hitting that time frame,” Jenkins told BioCentury.

To do this, DARPA is combining the advances it helped create in nucleic acid vaccines with rapid identification of antibodies, and hoping to use new delivery technologies.

P3 has three elements: new ways to grow viruses for testing and evaluating countermeasures; rapid identification and maturation of antibodies AbCellera is pursuing; and technologies to deliver nucleic acid constructs into patients that encode the antibody and produce a protective response.

The idea, Jenkins said, is to “use that RNA that we've been investing so heavily in as a vaccine modality and just encode the antibody sequence on the RNA and just to deliver the RNA directly into your muscle cells.” The human body would replace bioreactors (see "DNA-encoded and RNA-encoded antibodies").

RNA is easier to manufacture than a protein, so it could be manufactured at scale more quickly, she said.

Few groups are manufacturing RNA and DNA, but Jenkins said she is confident manufacturing challenges will be overcome quickly.

“The biggest barrier right now to the use of DNA or RNA is its delivery, and that has always been our biggest technical challenge around these in these programs,” she said. Clinical studies have demonstrated that RNA can be administered intravenously, but that isn’t an ideal delivery mechanism for a pandemic response.

“That is absolutely going to be a lot of the focus of the remainder of the P3 program,” Jenkins said.

In addition to rapid discovery and manufacturing, meeting the 60-day goal will require collapsing the regulatory timeline.

“While we do not anticipate that this platform would receive pre-approval we could anticipate a situation where once the RNA or DNA technology has been used in a number of clinical trials many of the studies that are typically required could be trimmed or not performed,” Jenkins said.

She envisions circumstances in which the “only component of the new treatment that is being changed is the sequence of the target antibody, the RNA or DNA and their formulations would remain entirely the same as they had in previous clinical studies. This might allow for proceeding to clinical studies without certain time-consuming animal studies which would greatly decrease the time it takes to begin Phase I clinical safety studies.”

Further analysis of the coronavirus crisis can be found at https://www.biocentury.com/coronavirus.