Ending Pandemic Disease
by Ivan Amato
A MOONSHOT TO END PANDEMICS Prominent in humanity’s list of dire scenarios is the constant threat that an infectious disease outbreak, such as the infamous 1918 Spanish flu, could grow into a global pandemic that kills tens of millions of people and wreaks economic havoc. Over the past century, urbanization, growing populations, and ease of travel have intensified the threat. The time is now to develop technology platforms that can quash most if not all infectious outbreaks before they can grow into global public-health wildfires.
THE PHILANTHROPY OPPORTUNITY It is estimated that economic losses due to a moderate to severe pandemic would top $570 billion per year. Currently, epidemics, which are serious but more localized disease outbreaks compared to global pandemics, cost the world about $60 billion annually. Philanthropists could help move humanity closer to ending the threat of pandemic disease with investments in organizations devoted to research and technology development in disease detection, surveillance, monitoring, diagnostics, vaccines, therapeutics, and other countermeasures.
On the otherwise light news day of December 9, 1979, nineteen members of a World Health Organization (WHO) commission signed their names onto a piece of parchment. On it, in six languages, remains one of the century’s most uplifting proclamations: “We, the members of the global commission for the certification of smallpox eradication, certify that smallpox has been eradicated from the world.” It is the only proclamation of its kind … so far. Smallpox, an infectious virus that killed an estimated 300 million people in the 20th century alone, had been erased from the list of public health concerns. It took a global vaccination campaign that began in 1959 and cost some $300 million, but the public health community had scored the first and still only eradication of a dreaded infectious disease.
Eradicating smallpox was a moonshot project if there ever was one, but now the most ambitious public-health practitioners among us say it is in within reach to take the entire threat category of pandemics off humanity’s table. Not just the threat of smallpox. Not just that of polio, which is on track to becoming the second infectious disease to be eradicated from the world. Not just the perennial threat from the ever-mutating influenza virus, the most famous pandemic of which killed some tens of millions of us one century ago. Not just the threat of HIV/AIDS, which has killed some 35 million people. Not just threats from Ebola, Dengue Fever, Zika, SARS, chikungunya, MERS-CoV, and Mayaro virus. But also the unending threat of “Disease X,” the public- health designator for as-yet-undetected infectious agents that this very second could be emerging in animal hosts or bioterrorism laboratories, setting the stage for a leap into its first human hosts.
“You can say it sounds hard, and it’s ambitious, and it’s crazy,” said Matthew Hepburn, a physician, biomedical engineer, just-retired Army colonel, and field-toughened public health professional who until this month had been running the Pandemic Prevention Program (P3) at the Defense Advanced Research Projects Agency (DARPA). “But I challenge you to say, ‘Why not?’ Why are we, as a society, not putting incredibly more effort into taking these diseases off the table, if we have the scientific know-how to do so.”
“It sounds audacious,” concurred virologist Richard Hatchett, CEO of the Coalition for Epidemic Preparedness Innovation (CEPI) and former director of the U.S. government’s Biomedical Advanced Research and Development Authority (BARDA). Even so, he said, “I think we have the technical tools to develop countermeasures against most, if not all infectious diseases we face today.” CEPI was established by a collection of governments and foundations soon after the 2014–2016 Ebola outbreak in West Africa had ended, but not before the virus had infected 28,616 people and killed 11,310 of them in Guinea, Liberia, and Sierra Leone. The outbreak also spread to seven other countries, causing an additional 36 cases and 15 deaths.
And that is just one outbreak of one infectious disease. According to WHO, between 2011 and 2017, the world experienced 1307 epidemic events involving 20 infectious diseases in 172 countries.
THE DEEP DISCOUNT OF PREVENTING PANDEMICS
The economic incentives to do what it might take to reduce or end the threat of pandemics are enormous. According to a 2016 report by the Commission on a Global Health Risk Framework for the Future and published by the U.S. National Academy of Medicine (NAM), “the annualized expected loss from potential pandemics is more than $60 billion.” One recent analysis of the potential costs of a Spanish-flu-caliber pandemic, published in the Bulletin of the World Health Organization, projected 720,000 annual deaths and an annual economic loss of $500 billion. Current U.S. investment in research toward a universal flu vaccine, which would be effective against all flu viruses (unlike the seasonal flu vaccines that are more or less effective against the predominant flu strains of any given year), falls within the $100 million to $200 million range, said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, at a meeting of the American Association for the Advancement of Science in February. The 2017–2018 flu season caused almost one million hospitalizations and 80,000 deaths. He described this “pre-pandemic” experience as “a wakeup call” that helped spur legislative momentum toward doubling research in pursuit a universal flu vaccine. The flu is just one disease with pandemic potential. Each of 11 priority infectious diseases identified by WHO in 2018 carries its own vast mortality and economic-loss potential.
Compared to these economic and human losses as result of pandemics the projected costs for developing vaccines seems paltry. A study published in 2018 in The Lancet, Global Health put the average cost of identifying a successful vaccine candidate from preclinical candidates for the infectious epidemic diseases that WHO prioritized in 2014 from $319 to $469 million. Ushering “at least one vaccine through the end of phase [IIa] trials for each of these 11 diseases would cost a minimum” of $2.8 to $3.7 billion, according to the authors. Phase IIa clinical trials test the efficacy of a medicine in patients with the condition to be treated; larger Phase III clinical trials roll out the tests into affected populations during an actual outbreak.
While acknowledging the uncertainties in “modeling the risks and potential impact of infectious disease crises,” the Commission on a Global Health Risk Framework for the Future proposed in the NAM report that “incremental spending of about $4.5 billion per year” would be more than prudent and amounts to only “a fraction of what we spend on other risks to humankind.” The commission recommended devoting $1 billion to accelerating R&D on vaccines, therapeutics, diagnostics, and other countermeasures and $3.5 billion to bolstering national public health systems. “If we spend too little, we open the door to a disaster of terrifying magnitude,” the commission wrote in its report The Neglected Dimension of Global Security: A Framework to Counter Infectious Disease Crises.
“To my mind, there are no insuperable barriers to developing vaccines or even therapeutics” for the WHO priority diseases, said CEPI’s Hatchett. For its part, CEPI is administering programs seeking epidemic-stopping vaccines for six infectious diseases — MERS-CoV, Lassa, Nipah, Rift Valley Fever, Chikungunya, and Disease X. The organization has a current and growing budget of some $750 million with, according to its website, “multi-year funding from Norway, Germany, Japan, Canada, Australia, the Bill & Melinda Gates Foundation, and Wellcome [Trust]” and “single-year investments from the governments of Belgium and the UK.” Additional support from philanthropists and other sources could enable the organization to expand the portfolio of diseases.
“We can prevent outbreaks from becoming an epidemic or pandemic,” said Hatchett. “There is just a lack of investment and a lack of political will.” In an interview, he stressed that in addition to the biomedical challenges of rapidly developing new vaccines and other countermeasures to infectious disease threats, nonscientific elements including regulatory oversight and approval, licensure, the presence of conflict in affected regions, and fear and distrust of vaccines and other medical interventions in some populations all play into the success or failure of vaccination campaigns.
A CHALLENGE FIT FOR DARPA
It was just one year after Matthew Hepburn began his tour of duty as a DARPA program manager that the worst Ebola outbreak yet swept through West Africa. The global response, he said, was “too little, too late,” especially because an experimental Ebola vaccine had been available. But it was only during the outbreak, rather than before, Hatchett added, that the necessary steps of performing clinical trials began. “It took months to set up a clinical trial infrastructure, clinical protocols, develop financing, and take things through the relevant regulatory and ethical review boards,” Hatchett said. “There were sources of delay that with proper planning could have eliminated.” Without these delays, thousands of lives might have been saved.
Hatchet laments that the opportunity was lost in the West Africa Ebola outbreak to deploy the candidate vaccine developed by Merck, known as rVSV-ZEBOV-GP. Not so for the subsequent and ongoing Ebola outbreak in the Democratic Republic of the Congo where more than 2500 cases and nearly 1700 deaths had been reported by the middle of July. As of late June 2019, according to Science magazine, some 130,000 doses of the vaccine, also known as V920, had been deployed. Preliminary efficacy rates for the vaccine appear to surpass 97%. And CEPI is also now funding researchers to investigate the VSV vaccine as a more general platform for countering Nipah and Lassa viruses, which are among the class of pathogens known as filoviruses. Ebola and Marburg also are filoviruses.
“If some nasty filovirus were to emerge, I think the first place we would go is through the Merck platform to stick glycoprotein onto it and see if we had active vaccine against the new virus,” Hatchett said. Different glycoproteins, which are complex biomolecules, can act like molecular flags marking specific viruses for removal by the immune system. Said Hatchett: “This is an example where everybody has accumulated a lot of experience and is essentially comfortable with the VSV platform and now it is available for at least certain classes of virus in the future.”
DARPA and CEPI are aligned in the overall mission to take out pandemic threats. DARPA is all about coming up with new approaches and rapidly funding and demonstrating proofs of concept. CEPI is all about ushering fundamental innovations through the downstream innovation process that leads to industrial-scale processes and millions of doses of deployable vaccines and other countermeasures. Said Hatchett: “If DARPA can bring forward some of the technologies out of Mat’s programs to the preclinical proof of concept stage, and these are ready to be turbo-charged with a big investment, that is the point at which CEPI likes to pick things up.”
For his part at DARPA, Hepburn had been overseeing a half-dozen programs, collectively drawing some $50 million of research support each year, which he is betting can help move the dial in humanity’s favor against pandemic challenges. With this program portfolio, DARPA is trying to make headway on many facets of a pandemic threat and response — early detection of infectious agents, rapid diagnosis, modeling how infections spread, and production and deployment of medical countermeasures with unprecedented swiftness.
In one of the programs, dubbed In Vivo Nanoplatforms, researchers are seeking to develop, according to DARPA, “new classes of adaptable nanoparticles for persistent, distributed, unobtrusive physiologic and environmental sensing, as well as the treatment of physiologic abnormalities, illness, and infectious disease.” In another anti-pandemic program, researchers hope to develop a rapid response that would slow the initial spread of outbreaks. The idea here is to develop a dialysis-like, post-infection therapy to filter hordes of pathogenic virus particles out of the blood of infected individuals. The point of this approach, Hepburn explained, is to “give a leg up to the immune response” before an infectious virus can establish its own beachhead in the patient’s body and from there to others.
STEPS TOWARD A PANDEMIC SPOILER
The most ambitious DARPA program that Hepburn initiated, the Pandemic Prevention Platform (P3), is going for the gold even as he makes his own professional transition to the Joint Program Executive Office for Chemical and Biological Defense (JPEO-CBD) at Fort Detrick, Maryland. The goal of P3 is to develop a comprehensive technology platform that can deliver, within 60 days of the detection of an infectious disease outbreak, a stop-gap antibody-based therapy that can keep an infection and its associated contagion at bay long enough in individuals and vulnerable populations to prevent an outbreak from spreading into an epidemic or pandemic. “The antibodies produced in response to treatment would only be present in the body for weeks months,” according to a DARPA statement. “This is consistent with DARPA’s intent to safely deliver transient immunity, halting the spread of disease by creating a firewall, and buying time for longer-term medical responses [such as vaccines] to be developed and deployed.”
“There are millions and millions of different versions of antibodies circulating through our bodies at all times,” Hepburn told The Moonshot Catalog, referring to the molecular interceptors the immune system churns out once the system’s reconnaissance and first-response cells (B-cells and T-cells, respectively) have identified a microbial threat. Following such an identification, the immune system initiates an iterative process that leads to antibodies optimized for tagging the threatening bacterial or viral particles. With these pathogen-tagging antibodies in circulation, more muscular components of the immune system, such as killer T-cells and macrophages, can find the pathogenic particles and take them out.
“We know how antibodies work. We know their structures. We know how to make them in big vats,” said Hepburn. “We want to use all of that knowledge and technology to solve the infectious disease problems.” The strategy P3 researchers are pursuing is to deliver to infected or vulnerable individuals the genetic instructions to, as Hepburn explained it, “immediately begin producing protective antibodies against a given threat.” For each disease, the instructions would derive from antibodies harvested from a person who gets infected during an outbreak but survives. In effect, the strategy transfers the immunological discoveries made naturally inside of a survivor’s body to the bodies of others exposed to or already infected by the disease agent.
“Can I give you a piece of DNA, or a piece of RNA, and can I put them in your muscle cells so that your muscle cells say, ‘OK, got it, I am going to make an antibody that is so protective that you are not going to get sick,’” Hepburn asked from a cellular point of view. With a smile, he said that researchers in his program have provided the answer: yes.
“This sends chills up and down my spine,” Hepburn said. “We proved the concept. Now we need to birth the baby. If we are going to take pandemics off the table, we need to put this together as a platform that can go from start to finish … from the identification of pathogens to massive doses of countermeasures.” With a practical P3 technology available, he said, the public health community would be able to thwart what otherwise could become a global catastrophe like the 1918 Spanish flu pandemic.
The Bill & Melinda Gates Foundation long has had vaccine development, particularly flu vaccine, in its public-health agenda. Now serving as the foundation’s director of Innovative Technology Solutions is Dan Wattendorf, who previously had been a DARPA program manager. There he championed programs in, among other things, immunoprophylaxis by gene transfer, a foundational component of Hepburn’s P3 program. Like Hepburn and Hatchett, Wattendorf is upbeat about humanity’s chances of securing a winning hand against pandemic disease. Regarding the conjecture that the quest to end pandemics has become a credible pursuit, Wattendorf said “I definitely think it is true.” But he added a cautionary perspective based on his respect for the creative forces of evolution. Said Wattendorf: “We always will have pathogens around us that will continue to evolve, so it is a perpetual arms race.”
More than at any time in history, humanity is now equipped for the challenge, Wattendorf said, pointing primarily to three scientific developments — genetic sequencing, gene therapy, and the ability to compartmentalize biological studies down to a single cell.
“It has become possible to read the adaptive immune response with the tools of genetic sequencing,” he said. He is referring to the ability to identify specific genetic instructions associated with the “learning curve” the immune system undergoes, usually over a course of weeks or months, to hone ever-more effective antibodies against an infectious bacterium or virus. Amazingly, he noted, this laboratory ability now is applicable on a single-cell basis. That makes it possible to isolate and characterize different antibodies made by a thousand or even a million different B-cells. The third important prong of Wattendorf’s triad of developments is the ability to add genes to cells, including genes that encode antibodies against specific pathogens.
Given these abilities, Wattendorf asks rhetorically, “Why not save time, and just give people the correct [antibody] response” to a pathogen even before they become infected. The concept, much like the one underlying the P3 program, is to “give the genes for the best antibodies to those who have not yet been exposed to the associated pathogen.” Wattendorf started down that road several years ago when he was at DARPA running a program known as ADEPT. In that program, several “RNA companies,” among them Moderna in Cambridge, Massachusetts, began developing technology platforms to make this capability broadly applicable.
“This is a capability that would conceivably allow us to move forward rapidly to protect against any infectious disease,” Wattendorf said. Whereas DARPA programs are driven by national security concerns and the imperative to keep warfighters healthy enough to carry out their missions, the Gates Foundation focuses on affordably reducing the social and economic costs due to endemic diseases, such as HIV, tuberculosis, and malaria. Here, large-scale treatments based on antibodies and other so-called biologics — among them RNA, DNA, and proteins — are not yet practical.
“The cost of making biologics is something like $100 to $130 per gram,” Wattendorf noted. “To be able to make [HIV-neutralizing] antibodies, we would need to make them at $10 gram.” In February, with Gates Foundation backing, Inovio Pharmaceuticals, in collaboration with the Wistar Institute and the University of Pennsylvania, announced it had embarked on the “first-ever human study” of its “DNA-encoded monoclonal antibody (dMAb™) technology.” The trial is designed to evaluate the approach for its ability to prevent or treat Zika virus infection. “When delivered directly into the body, the genetic codes provided by the synthetic dMAbs, instruct the body’s cells to become the factory which manufactures the therapeutic antibody products,” the company explained in a statement.
TECHNOLOGY IS JUST PART OF THE SOLUTION
If the threat of pandemic disease can be reduced or even eradicated, technology will be only one of the important factors and it will take many collaborators. “The responsibilities and capabilities that would need to be brought to bear to prevent a future pandemic are not situated within any single organization,” said Hatchett. “You have to have a well-functioning ecosystem and set of alliances to have any aspiration to prevent future pandemics.” The ecosystem includes players that can deliver many functions such as disease surveillance and detection, countermeasure discovery and development, financial support, licensure, manufacturing, stockpiling, and delivery.
Ending Pandemics, an organization established in 2018 with seed funding from the Skoll Global Threats Fund (SGTF), has taken on early detection as its raison d’etre. “A focus on detection … allows outbreaks to be stopped quickly at their source,” the organization’s president, Mark Smolinski, told The Moonshot Project in an email exchange. Three out of four epidemic and pandemic threats in humans are contracted from infected animals, Smolinski noted. As such, he said that “if we prioritize our efforts to find outbreaks faster in animals, it is possible to prevent human infection altogether.”
The organization’s flagship project, known as Participatory One Health Disease Detection (PODD), relies on smartphone and web applications developed earlier in the decade with a $2 million grant by SGTF to Chiang Mai University in Thailand and with input from veterinarians, public health officers, livestock officers, community volunteers, technologists, economists, social scientists, and geographic information systems (GIS) experts. In the hands of volunteers, these tools support, in Smolinski’s words, “community-based reporting for early detection of emerging infections in livestock, wild animals, and humans.” Reports from volunteers using the PODD mobile app alert local health experts who then collect lab samples from the putative disease source and then, using the data from those samples, can initiate vaccinations and other preventive measures.
In Thailand where the PODD framework was first rolled out, more than 10,000 “abnormal events” were reported as of the end of the last year. “An outbreak of foot and mouth disease was rapidly detected and contained, saving the local economy an estimated $4 million,” Smolinski noted to illustrate just one of the expected payoffs. In the coming years, he and colleagues expect to expand the PODD approach to neighboring countries, among them Cambodia and Indonesia. Tanzania already has adopted a related approach based on the PODD model. “As a result of this community-based surveillance approach, the time to detect an outbreak in pilot districts has reduced from 30 to 7 days and community attendance at health clinics has increased,” Smolinski wrote. “If we act together and make this a global priority, we can stop outbreaks at their source and remove the prospect of global spread.” While grateful for the seed support from SGTF, Smolinski invites participation of other “visionary donors,” noting that “the goal of eliminating this global threat is greater than any one single donor could ever tackle.”
Wattendorf envisions another crucial role for smartphone and internet apps and tools: fear management. Even more than the infectious agents itself, he suggested, fear can destabilize borders, security, people’s daily living and activities, and the abilities of governments and industry to carry on normally. The messages people receive during a spreading outbreak should be framed to specific populations in accordance with their educations and actual risk, he said, adding that he would like to see more research into challenges such as targeted public health messaging. “Cell phone coverage of the world is getting better and better, so it should be possible to deploy targeted messaging in outbreaks that not only deals with those at risk, but that also deals with the fear that spreads so rabidly,” Wattendorf said.
One of the most astonishing realities about the quest to end the threat of pandemic disease is that many of those who are best positioned to judge the practicality of the goal actually believe it is attainable. “I do not think it is a crazy idea,” Nancy Messonier, Director of the National Center for Immunization and Respiratory Diseases (a unit of the U.S. Centers for Disease Control and Prevention) said at the AAAS meeting earlier this year. “If you don’t shoot big, how are we ever going to get there?”
“I challenge you to say, ‘Why not?’ Why are we, as a society, not putting incredibly more effort into taking these diseases off the table, if we have the scientific know-how to do so.” — Col. Matthew Hepburn, former program manager, Defense Advanced Research Projects Agency
In an interview, Hepburn doubled down on his conviction that it will be possible to develop a generic and rapid ability to quash whatever pandemic threat that nature or ill-willed human beings might muster. “We can’t negotiate with Mother Nature and say we would like another 6 months to work up our countermeasure,” he said. “To deal with pandemics, we need to hit the 60-day mark, and I am profoundly excited because I think we can do it.”
Adds Hatchett: “After decades of dealing with emerging and emergent infectious diseases, which have been tremendously disruptive with tremendous amounts of mortality and economic disruption and dislocation, the world finally has become sensitized to this threat. Finally the world has recognized this is not a SARS problem, or an Ebola problem, or an H5N1 problem [pandemic flu], but that this is an emerging infectious disease problem and we have to have a set of standing capabilities and standing relationships that we can call on whatever the threat is.”
Perhaps on some otherwise light news day in the future, a commission comprised of members from the many organizations of the innovation ecosystem taking on the threat of pandemics will scrawl their names on a seal-embossed document with the following inscription: “We, the members of the global commission for the certification of the end of pandemics, certify that the threat of pandemic disease and the humanitarian and economic devastation traditionally associated with it, has been eradicated from the world.”
Ivan Amato is a writer, editor, podcaster, and science cafe host based in Hyattsville, Maryland. He is the editor of The Moonshot Catalog.