A Crisis Gives You WIngs

The latest and largest Ebola outbreak showed the importance of anticipating epidemics. The new Coalition for Epidemic Preparedness Innovations is doing just that by developing vaccine candidates against top pathogens with pandemic potential.

By Michael Dumiak

The hot equatorial spring in Guinea in 2015 was still a shell-shocked place to be, with the western African nation and its immediate neighbors dazed from the Ebola outbreak that began a year earlier and put the entire world on edge. John-Arne Røttingen, Gunnstein Norheim, and Byorg Nilssen recall it well, as it was at that time they helped launch an efficacy trial of an Ebola vaccine candidate.

Two years later, these three Norwegian public health workers are in a vanguard looking to develop vaccines against other emerging pathogens with epidemic potential. They are just part of an international team that debuted the Oslo-based CEPI organization, the Coalition for Epidemic Preparedness Innovations, at the World Economic Forum this past January with US$540 million in funding and a mandate to bring new vaccines to bear against priority pathogens.

Building on the lessons of the 2014/15 Ebola epidemic, the coalition is the latest try at putting in place a mechanism to prevent epidemics or pandemics before they start and to respond to them more effectively when they do. CEPI looks to join other organizations in filling the gaps in vaccine development produced by an unbalanced system of global capitalism, in which there isn’t economic incentive to develop costly vaccines without developed country markets to support them. Global health experts want a store of vaccine candidates with potential for rapid development, much like what the Ebola crisis produced albeit in an ad-hoc manner.

CEPI plans to fund new vaccine candidates from development, through preclinical research, to proof of principle in humans. At that point the candidate will wait, much like a fire extinguisher behind a glass pane, to be broken out at the right time. When an outbreak occurs, an existing vaccine candidate could be rushed into efficacy testing and at a greatly accelerated pace toward manufacture and deployment.

Ebola showed even a small outbreak has global consequences. CEPI aims to be a kind of insurance system against other emerging pathogens so that the somewhat chaotic but ultimately successful response to Ebola isn’t repeated. So far, the Coalition has had a remarkable run. In a little over 12 months it set a list of priority pathogens, raised $540 million in funding, is now reviewing 30 grant applications, and just hired a full-time chief executive, Richard Hatchett, the former chief medical officer and deputy director of Biomedical Advanced Research and Development Authority (BARDA; see Q&A).

Ebola: lessons learned

John-Arne Røttingen is in a cab moving slowly through Washington, DC, horns blaring around him. That morning, he had discussions with Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH), and then with officials at BARDA. That evening included an event with members of Congress and likely members of US President Trump’s cabinet.

These are just a few of the long list of conversations with government donors and potential collaborators Røttingen has had over the last six months in his post as interim head of CEPI. In April he will lead the Research Council of Norway. Meetings with government officials in Oslo, Berlin, and Tokyo helped secure commitments of $340 million, while the UK’s Wellcome Trust and the Bill & Melinda Gates Foundation each added $100 million. The European Commission has also pledged around $250 million, which would make CEPI’s total funding $790 million. Norway’s National Health Institute and the Indian Department of Biotechnology in New Delhi are also contributing infrastructure and support. But they haven’t crossed the finish line yet. The funding goal for CEPI is a billion dollars, and Røttingen remains confident they will get there.

Røttingen was deeply involved in the Ebola response, along with his Norwegian Institute of Public Health (NIPH) colleagues: virologist/vaccinologist Gunnstein Norheim and project manager Bjørg Dystvold Nilsson. Nilsson helped coordinate the large efficacy trial of the leading Ebola vaccine candidate, while Røttingen and Norheim helped to implement it. On the ground in tented clinics in Guinea, from the World Health Organization (WHO) in Geneva, and within the pharmaceutical multinational Merck, dozens of people helped to initiate the 12,000-person ring trial of the rVSV-ZEBOV vaccine candidate (see IAVI Report, Vol. 19, No. 4, 2015). Late last year the recombinant viral-vector vaccine, which uses an altered vesicular stomatitis virus to express a protein from the Zaire strain of Ebola virus, showed 100 percent efficacy. The candidate was manufactured and advanced into clinical trials by Merck after being developed by the Public Health Agency of Canada and the biotech company NewLink Genetics. It is currently under expedited review by the US Food and Drug Administration.

Even as Ebola wound down, the impact of this outbreak lingered. In addition to killing 11,300 people out of 28,600 cases in six countries, Ebola raised a lot of questions for public health officials worldwide. The WHO held an Ebola Special Session of the Executive Board in Geneva in January 2015 to try to understand what exactly had gone on during the outbreak. The Ebola response also topped the agenda at the WHO annual meeting in May that year, which commissioned an Ebola Interim Assessment Panel. This panel issued its final report in July, to which the WHO Secretariat responded a month later.

Depending on your frame of reference, the response to the Ebola epidemic of 2014/15 was either a great success or startlingly slow and ineffective. Critics said the outbreak should have been foreseen. Dire estimates circulated as the epidemic raged with some predicting the dead would soon number in the thousands, perhaps as many as 10,000 a week by the end of 2014. But the thousands of dead per week never did materialize. Effective quarantining, local heroism, government interventions, a huge volunteer response, and public health practices such as publicizing effective hygiene, building sufficient clinics, and providing quality training for health care workers proved enough—eventually—to bring the epidemic under control.

As the outbreak raged, pharmaceutical companies Merck, GlaxoSmithKline (GSK), and Janssen brought viable vaccine candidates and an experimental antibody therapy against Ebola into the field at an incredibly rapid pace. It took less than a year from when a few American and Liberian health workers received the only existing doses of an experimental antibody treatment in 2014 to the start of the efficacy trial of the rVSV-ZEBOV vaccine candidate that involved thousands of people. Decisive actions made this happen. Public and private institutions partnered in unprecedented ways to develop and manufacture these Ebola vaccine candidates. This was in large part possible because the pharmaceutical companies weren’t starting from scratch. The vaccine candidates were in stasis, waiting for the need to emerge and organizations with better resources to carry them forward.

But what should be done about the next pandemic: one for which no ready-to-be-tested vaccine candidates exist? “One future option would be developing vaccines and antivirals for emerging pathogens to the point of preclinical development or perhaps Phase I safety testing,” Vincent Racaniello, a Columbia University immunologist, blogger, and host of the This Week in Virology podcast told IAVI Report in the immediate aftermath of the Ebola pandemic. “Then they’ll be stored until an outbreak happens.”

This was the topic discussed in Geneva at the WHO headquarters in October 2015, a few months after the Ebola panel report was released and three months after an op-ed in the New England Journal of Medicine from Stanley Plotkin, Adel Mahmoud, and Jeremy Farrar called for a global vaccine development fund. These WHO discussions led to the concept of CEPI.

By last summer, John-Arne Røttingen accepted a call from the WHO and began putting together a business plan for this new coalition. CEPI’s scientific advisory team was ready by August (see sidebar, below).

The Scientific Advisory Committee

The Coalition for Epidemic Preparedness Innovations (CEPI) is guided on science themes by a panel of nearly 30 top experts in vaccines and public health. The Scientific Advisory Committee, chaired by Mark Feinberg, chief executive officer of the International AIDS Vaccine Initiative, advises CEPI on scientific matters related to research and development, ruling on technical content for proposal requests, and designing the criteria by which applicants are granted funding. Along with Feinberg, the current team includes the following individuals as well as five non-voting members: Heinz Feldmann, US National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases Kathleen Nuezil, University of Maryland Peter Smith, London School of Hygiene and Tropical Medicine Alan Barrett, University of Texas Medical Branch George Fu Gao, Chinese Center for Disease Control and Prevention Gunnstein Norheim, Norwegian Institute of Public Health Stanley Plotkin, VaxConsult Maharaj Kishan Bhan, Jawaharlal Institute of Postgraduate Medical Education and Research Jesse Goodman, Georgetown University Helen Rees, Wits Reproductive Health and HIV Institute in South Africa Daniel Brasseur, consultant Penny Heaton, Bill & Melinda Gates Foundation James Robinson, James Robinson Biologics Consulting Jean-Francois Delfraissy, L’Agence nationale de recherches sur le sida et les hépatites virales (ANRS)/French National Institute of Health and Medical Research Gagandeep Kang, India Department of Biotechnology Amadou Sall, Institute Pasteur Dakar Gary Disbrow, Biomedical Advanced Research and Development Authority Subhash Kapre, Inventprise Connie Schmaljohn, US Army Medical Research Institute of Infectious Diseases Bernard Fanget, Abivax/Neovacs David Kaslow, PATH Michael Kurilla, NIH Kenji Shibuya, Department of Global Health Policy, University of Tokyo Non-voting members: Bernadette Murgue, World Health Organization; Ali Alloueche, Takeda; Kathrin Jansen, Pfizer; Jean Lang, Sanofi Pasteur; Johan Van Hoof, Johnson & Johnson

With a business plan in hand and the science board in place, Røttingen could knock on doors at health ministries and large philanthropic organizations, this time with a purpose: raising a billion dollars.

Meanwhile the scientific advisory team began selecting CEPI’s first targets. They did so by winnowing down a list of pathogens most prone to generate epidemics that was already established by the WHO as part of its R&D Blueprint. Last spring, the WHO’s Product Development for Vaccines Advisory Committee produced thorough pipeline analyses for 25 of these pathogens (Vaccine 34, 2863, 2016). CEPI’s science team then zeroed in on what the WHO describe as the top 11 pathogens in the world needing urgent R&D attention (see sidebar, below).

Pressing pathogens

These 11 pathogens require urgent consideration, according to the World Health Organization (WHO). From this list, CEPI chose its first three targets: Nipah, Lassa fever, and MERS (shown in bold). Descriptions for these pathogens were compiled from information provided by the WHO and the US Centers for Disease Control and Prevention. Crimean-Congo hemorrhagic fever: an infection caused by the tick-born Nairovirus and spread by contact with infected blood or the insects themselves. Symptoms include fever; back, joint, and stomach pain; severe bruising; and uncontrolled bleeding. Case fatality rate is from 10 to 40 percent. Ebola virus disease (formerly Ebola hemorrhagic fever): infection caused by one of four strains of Ebolavirus species found in several African countries and transmitted by direct contact with blood, bodily fluids, contaminated objects, infected monkeys or bats or, possibly, with semen from a man who’s recovered from the infection. Symptoms include fever, diarrhea, vomiting, and unexplained hemorrhaging. Case fatality rate averages 50 percent; in past outbreaks fatality rates ranged from 25 to 90 percent. Marburg hemorrhagic fever: caused by a virus hosted in the African fruit bat Rousettus aegypticus, it is not known how the virus is transferred to humans. Causes fever, chills, headache, myalgia progressing to jaundice, delirium, weight loss, massive bleeding, and organ failure. Spreads from human to human by contact with bodily fluids or contaminated objects. Case fatality rate ranges from 24 to 88 percent./p> Lassa fever: viral illness caused by a single-stranded RNA member of the family Arenaviridae. Transmitted by ingestion or inhalation of virus shed in droppings and urine of Mastomys natalensis, the multimammate rat found in west, central, and east Africa. Symptoms include malaise and headache progressing to shock, respiratory distress, and hemorrhaging in gums, eyes, nose, or mucous membranes. Overall fatality rate is about one percent, but during outbreaks the fatality rate can reach 50 percent. MERS/SARS: MERS (Middle East Respiratory Syndrome) is caused by the single-stranded RNA virus of the genus Betacoronavirus. Related to SARS (Severe Acute Respiratory Syndrome), another coronavirus-caused disease on the WHO list of 11. Both prompt fever, cough, shortness of breath, and are not always, but often fatal. Researchers think MERS may have originated in bats, but that the true reservoir of the virus is camels. Like SARS, MERS is believed to spread by close contact with ill people, moving via respiratory secretions. Fatality rate is about 30 percent, though this data may be underreported. Nipah: this virus is part of the Paramyxoviridae, distributed through southern Asia, India, and Australia, and is transmitted from bats, pigs, and other Nipah-infected people. Transmission also happens when people have direct exposure to infected bats, for example by drinking raw date palm sap contaminated with bat secretions. Symptoms include fever and headache, followed by drowsiness and disorientation. Nipah is associated with encephalitis. Fatality rate is 74.5 percent. Rift Valley fever: viral disease caused by a member of the genus Phlebovirus. Carried in livestock through eastern and southern Africa and thought to spread by contact with blood, tissue, or bodily fluid of infected animals and by mosquitoes. Symptoms are most often mild, but in some cases (8 to 10 percent) can cause encephalitis, blurred or loss of vision, and hemorrhagic fever. Fatality rate is one percent. Chikungunya: a viral fever transmitted among humans from bites by the Aedes aegypti and Aedes albopictus mosquitoes, the same mosquitoes that transmit dengue virus. It is seldom fatal, but can cause severe muscle and joint pain along with fever. Severe fever with thrombocytopenia syndrome: a newly emerging infectious disease caused by a phlebovirus carried by ticks. Symptoms include fever and thrombocytopenia (low blood platelet count). Up to 30 percent of cases in outbreaks studied so far were fatal. Zika: a virus spread among people by the Aedes aegypti and Aedes albopictus mosquitoes. Symptoms include muscle pain and headache, but are most often mild and it is not associated with any fatalities. Zika can, however, be transmitted from a pregnant mother to her fetus, and is a cause of microcephaly and other severe fetal brain defects. —MD

“Our objective was to designate two or three pathogens,” says Norheim, the Norwegian vaccinologist who coordinated CEPI’s scientific discussions as it came into being. “The real question from the start is how do you limit the scope? Which diseases? How many products? What is the consensus?” The factors the science board considered were: feasibility, innovation and application potential, time to completion, experience and track record, expected cost and available funding, and capacity building and potential. “There is no perfect decision,” Norheim says. “We just have to make a choice, do our best, and start with some of them.”

The scientific advisory board conducted a kind of quantitative gap analysis, weighing different factors such as how important it would be to demonstrate that the new venture could deliver among the pathogens they would select. Jim Robinson, a former Merck senior vaccine development executive, pointed out that novel platforms can slow down regulatory review. In some cases it might be better to trade novelty for speed. Also, CEPI did not want too much overlap, or at least where vaccine development efforts are underway, there should be some unique or clearly helpful role that the Coalition could play. CEPI’s scientific team eventually landed on prioritizing MERS (Middle East Respiratory Syndrome), Nipah, and Lassa fever (see sidebar, above), with the goal of developing two viable candidates for each of these pathogens. In choosing these three pathogens, the Coalition is aiming to cover infectious agents endemic to a broad and vulnerable swath of the developing world including the Middle East, western Africa, and subcontinental Asia.

In February, CEPI held a meeting in Paris to introduce the “CEPI Partners Forum,” advertising its first call for candidates against these pathogens. The coalition is also filling its vital experts database: the high-level experts who will review the grant proposals as they come in.

All three of these pathogens are the cause of recently reported outbreaks: MERS, first reported in Saudi Arabia in 2012, with nearly 2,000 cases confirmed across the Arabian Peninsula and a low-grade outbreak coming in January in the Saudi town of Buraydah; Lassa, first pinpointed in Nigeria with the death of two missionary nuns in 1969 with the most recent outbreak occurring in Togo and Liberia last year; Nipah, a recently emerged paramyxovirus with high fatality rates, has emerged on a near-annual basis in Bangladesh with 300 confirmed cases from 2001 through 2015.

The potential for devastating epidemics from just this deadly trio is alarming. These zoonotic pathogens are easily transmissible among humans. Nipah is endemic to a hugely densely populated part of the world, with two billion people living where the virus is already known to exist or where the Pteropus fruit bats that serve as the animal reservoir of the virus are found. The last real outbreak killed 100 people in 1999, but more than a million pigs were slaughtered before the virus was stopped. Lassa and MERS are in places that are only remotely accessible and in difficult straits politically. While for Nipah the US Centers for Disease Control and Prevention (CDC) says that a vaccine making use of Hendra G protein to produce cross-protective antibodies against both Hendra and Nipah has been used in Australia to protect horses (and may show promise in protecting against henipavirus in humans), its main advice to the two billion people living in the Nipah zone is to avoid exposure to sick pigs and bats and not to drink raw date palm sap.

CEPI’s first goal is to move new vaccines against these three pathogens through development from preclinical to proof of principle in humans. Its second focus is on “the development of platforms that can be used for rapid vaccine development against unknown pathogens.” Research and data produced for Nipah, for example, might have applications in developing vaccines against other paramyxoviruses.

Collaboration across sectors

Mark Feinberg, president and chief executive officer of the International AIDS Vaccine Initiative (IAVI), leads CEPI’s scientific committee. Feinberg brings his deep experience dealing with Ebola vaccine development to play in this role. During the last Ebola epidemic he worked for Merck, leading the coordination of the company’s collaborative development of rVSV-ZEBOV. Now with IAVI, and having spent time earlier in his career in academia and with the NIH, Feinberg hopes that CEPI will show the benefits of cooperation between private and public sectors to a wider community, elaborating on what happened with Ebola.

Merck’s vaccine wasn’t the only one to emerge from the Ebola crisis. It just happened to be the one furthest along in trials as the epidemic subsided. GSK also has a promising candidate, and the fearsome power of Ebola also drew the first tobacco-grown antibody treatment into field use. “It was an amazing and complicated experience. The speed with which it all progressed and the urgency with which people were motivated were unprecedented,” Feinberg says. “It was unusual to involve so many in a collaborative way between the private and public sectors to go after a global health threat. It was an important disease to target, but also one which was not a commercial opportunity and involved a lot of risks and opportunity costs for companies.”

This is where CEPI comes in. The coalition might be able to spur conversations among not-for-profit entities, government health and research bodies, and private-sector companies about the development of vaccines for which there is no commercial market. For Feinberg these conversations can’t come soon enough. “I’ve seen the same issues from different perspectives. I’ve seen opportunities for people working together more effectively across sectors. The Ebola experience, tragic as it was, served as a tipping point in thinking about how the private and public sectors need to work together to go after emerging infectious disease threats,” Feinberg says. “Ebola was just one of what is going to be a continuing experience. Before Ebola was even finished, Zika was on the rise. And there will be something to follow Zika. You can’t mobilize new teams and move from one crisis to another. We should be able to craft a way to have a robust, proactive, collaborative effort that gets the job done. I don’t see how we will be successful unless we figure that out.”

There may also be some lessons from CEPI’s launch for the HIV vaccine field. “When you go after the kind of issues CEPI is taking on, you’re creating something where something didn’t exist. People bring innovative thinking and frank discussion to the table,” says Feinberg. “When I reflect on where the HIV vaccine field is, it’s clear we can learn a lot from CEPI’s fresh approach. Progress towards an HIV vaccine would derive enormous benefit from the kinds of discussions that have taken place to create CEPI.”

CEPI’s launch

Months of preparation went into CEPI’s launch in Davos, but there was at least one influential person there who did not need to be convinced of the importance of what CEPI is trying to accomplish: Bill Gates. “The world is tragically unprepared to detect local outbreaks and respond quickly enough to prevent them from becoming global pandemics,” the Microsoft founder and co-chair of the Bill & Melinda Gates Foundation, said from Davos. “Without investments in research and development, we will remain unequipped when we face the next threat.”

Wellcome Trust Director Jeremy Farrar, representing another big CEPI funder, made the case for using vaccines to ward off these threats. “Epidemics are among the significant threats we face to life, health, and prosperity,” he said from Davos. “Vaccines can protect us, but we’ve done too little to develop them as an insurance policy. CEPI is our chance to learn the lessons of recent tragedies, and outsmart epidemics with new vaccine defenses.” Japan, through its health minister Yasuhisa Shiozaki, views CEPI as part of its vision of universal health coverage; Berlin’s Minister of Education and Research, Johanna Wanka, as part of the United Nations’ sustainable development agenda. “The Ebola crisis made us painfully aware of the gaps in the international health system,” Wanka said. “Prevention is the best means to ensuring healthy lives for all.”

Representatives of big pharma organizations leading the industry vaccine response were also on hand at CEPI’s launch in Davos, with GSK sending its outgoing chief executive, Andrew Witty. He described anticipating and preparing for future health threats as one of the greatest challenges of our time. GSK is spearheading a project called Biopreparedness Organization (BPO) in response. The plan is to build a Rockville, Maryland-based unit with a $40 million to $50 million annual budget on a ‘no profit, no loss’ footing, joining its new vaccines plant there. Luc Debruyne, GSK’s vaccine president, describes the future BPO as a permanent and dedicated facility to avail the company’s scientific expertise against emerging infectious diseases. Debruyne, penning a post about the BPO on LinkedIn, specifically pointed out his hope for it as a proving ground for faster vaccine development. GSK spokeswoman Catherine Hartley says the firm would welcome the creation of a network of approaches and projects—coordinated through a governing body such as CEPI—working on different threats simultaneously.

Neither GSK nor Merck has ongoing programs for MERS, Nipah, or Lassa fever, however, neither is ruling out their involvement. Merck spokeswoman Pamela Eisele says the company is actively engaged in discussions about how it can best contribute, and GSK is evaluating the CEPI requests for candidate proposals to see if the BPO can help contribute. Merck says it is also taking a broader approach. “Our responsibility does not end with the availability of a new vaccine,” Eisele says. “We collectively rely on sustainable health systems to make sure these vaccines reach the people they are intended for. As we have seen with the Ebola vaccine trials and with routine immunization programs, trust and confidence in vaccines, in delivery systems, and in the institutions and people that make decisions about vaccines is critical to success. Sharing knowledge, best practices, our own experiences, and working with stakeholders is another way we seek to support sustainable, resilient public health and health care systems and to prevent the next calamity.”

There might also be potential for CEPI to engage more with Indian vaccine developers and manufacturers. Gagandeep Kang, executive director of the Translational Health Science and Technology Institute in Faridabad, points out that India is building a large and growing domestic vaccine production industry. Pursuing Nipah, MERS, and Lassa via CEPI, Kang says, is an opportunity for India, and researchers in developing countries more broadly.

Filling gaps

CEPI is not the first public health initiative to come out of Davos. Myron “Mike” Levine, associate dean at the University of Maryland, recalls the debut of Gavi, the Vaccine Alliance, at Davos and his role as co-chair of a task force on R&D. Gavi serves as a funding and distribution agency for vaccines in the developing world. But Levine thinks CEPI could fill a vital gap left by Gavi. “Sometime in the future when the constellations align, there will emerge a pathogen with the severity of swine influenza from 1918 and 1919, with the ability to spread. It will be so infectious it will shut down cities and affect industrialized countries, as we saw with SARS [Severe Acute Respiratory Syndrome] and Ebola,” he says. “We saw what SARS did. Such a lesson. That’s why MERS is important. That kind of thing—the translation of the lessons of Ebola, Zika in its own right—is not what Gavi does.”

Gavi Chief Executive Seth Berkley was at Davos this year, extending a hand to CEPI. Preparing for epidemics ahead of time is in the global interest, Berkley says. “Gavi will work closely with CEPI to be sure vaccines that are relevant for developing countries have a market and are stockpiled, ensuring vaccines are available when the next epidemic strikes.”

These are major considerations, according to Laurie Garrett, global health fellow at the Council on Foreign Relations in New York City, where Røttingen recently spoke about CEPI. Garrett is no stranger to thinking about future pandemics as author of, among others, The Coming Plague: Newly Emerging Diseases in a World Out of Balance. Along with Richard Preston’s The Hot Zone, these two books set off alarm bells about coming pandemics that have been ringing for more than 20 years.

Garrett says there are a lot of questions that are reasonable to ask about the CEPI approach, even while by and large supporting it. “In my 30 years of being involved in epidemics, I’ve never seen one where we knew in advance that this was a likely target so we would be ready with a vaccine, except with Ebola. And that situation with Ebola was goosed by a set of bioterrorism concerns in the United States.”

This is part of the reason that CEPI is drawing on outside expertise and building partnerships. Fauci says staffers from NIAID and the US Department of Health and Human Services are already in touch with the group and participating in scientific advisory conversations. NIAID’s existing vaccine platforms can support development of candidates for the CEPI pathogen targets. NIAID has a years-old development program for Lassa fever, for example. “We’d certainly share our expertise and our knowledge,” Fauci says. “We’re doing work on paramyxoviruses, such as respiratory syncytial virus, and we’ve developed novel vaccine platforms using structural biology to develop immunogens.” Since Nipah is also a paramyxovirus, Fauci says, NIAID will lend CEPI some technology and advances, and the same thing holds true for MERS. “We can be an implementation and supplementation of the research component of what they do,” he says. “There’s always a little overlap. If they’re going to develop platforms for different vaccines, we have a major investment in platform technology. But I think it’s much more complementary than it is overlapping.”

Michael Dumiak reports on global science, technology, and public health and is based in Berlin.