Rapid Medical Countermeasure Response to Infectious Diseases: Enabling Sustainable Capabilities Through Ongoing Public- and Private-Sector Partnerships: Workshop Summary (2016)

6

Developing MCMs for
Coronaviruses

When the SARS coronavirus spread around the world in 2003, it resulted in more than 8,000 cases, nearly 800 deaths, and $50 billion in economic damage. During this time, understandably, there was short-term momentum for developing pharmaceuticals to combat SARS, said Tom Inglesby, director of the UPMC Center for Health Security. However, that momentum has long since waned, and there are still no products available to treat or prevent SARS. This poses a serious threat because the potential for SARS to reemerge persists, whether naturally or as a result of a research accident in a laboratory. In addition, there is no complete inventory of where the SARS virus is worked on around the world. More recently, another globally threatening coronavirus known as MERS emerged in 2012, leading to about 1,000 cases thus far and more than 400 deaths (Maurice, 2015). Similar to the SARS experience, 3 years after the first case, MCMs for MERS still do not exist.

In this chapter, panelists discussed the important period of opportunity for development and action prior to a virus reaching an emergency-level epidemic threshold. (Detailed technical accounts of the MCM development process are included at the end of this chapter in the Chapter 6 Annex.) Using coronaviruses as an example, speakers and participants introduced important concepts like One Health and the need for ongoing risk assessments and alternative product options to contain the spread of disease.

CORONAVIRUSES

A brief background on coronaviruses and an update on the status of the MERS coronavirus outbreak was provided by David Swerdlow, associate director for science at the National Center for Immunization and Respiratory Diseases at CDC (see Box 6-1).

Adapting Tools: Creating a Coronavirus Risk
Assessment Tool from IRAT

IRAT is a very useful tool because there are so many influenza viruses, Swerdlow pointed out, so a key challenge in creating a useful coronavirus risk assessment tool is the low number of identified coronaviruses in comparison. In addition, there were not enough data to grade the risk elements and not enough coronavirus experts to do the grading. The final conclusion of the exercise was that MERS was like SARS (especially before the transmissibility of SARS increased in later phases). Unfortunately, he said, the coronavirus risk assessment tool did not add much to the overall assessment of risk. Risk assessment is critically important, he stressed, but they found that IRAT could not be adapted for use with coronaviruses.

Assessing Coronavirus Threats at the Source

To stop the next SARS outbreak at its source, we need to know where it is coming from, said Peter Daszak, president of EcoHealth Alliance. With funding from Fogarty International Center at NIH, the EcoHealth Alliance sought to identify the wildlife origin of SARS. While crossover from civets into humans was of particular interest, the data suggested that civets are not the wild reservoir but instead are infected in the live animal markets of Southern China. Serology and phylogenetic analysis show that bats harbor a SARS-like coronavirus that is phylogenetically closely related to the human and civet SARS viruses (Li et al., 2005). The bat virus is a precursor, but is not the SARS that

infected humans. With funding from the U.S. Agency for International Development (USAID), Daszak and colleagues found there is a huge diversity of bat SARS-like coronaviruses. Researchers in China have identified novel bat coronaviruses that are more closely related to the SARS coronavirus. The S proteins of these bat viruses are able to bind to the human and civet angiotensin converting enzyme II, which is the receptor for the SARS virus (Ge et al., 2013). With funding from NIAID, EcoHealth Alliance continues to look across Southern China for these bat viruses, interviewing and taking samples from people potentially at risk (e.g., those trading bats in the markets, hunting bats, living in caves) to look for cases of spillover from the wildlife reservoir.

MERS-CoV Outbreak

Although MERS continues to be the clear and present danger of the coronavirus group, Daszak concurred with others that the general public in the United States is not aware of or concerned with an outbreak until it arrives on the continent (at which point there is typically significant media attention). Although there have been two MERS cases in the United States, there has been no secondary spread. Daszak cautioned, however, that this virus still poses a significant risk to the public’s health.

The wild reservoir of MERS is still unknown, he continued, although as discussed, there is good evidence that it is common in camels across Saudi Arabia and the whole of North Africa. However, even this is a spillover from the true wildlife reservoir, which some evidence shows to include bats as well (Memish et al., 2013). Juvenile camels are most likely to have MERS infection, and important cultural and virus transmissibility questions exist when considering the role of slaughterhouses, camel milk production, pet camels, racing, and camel beauty pageants. Daszak pointed out that it is extremely difficult to work in Saudi Arabia because of cultural differences and government restrictions, and in many other places where MERS has emerged or could do so. Although EcoHealth Alliance was invited in by the Saudi government, Daszak said that these connections are not secure, and long-term, sustainable methods are needed to work in unstable countries on important and potentially threatening viruses.

Daszak described ecological niche modeling, which can be used to deduce the MERS “epizone,” from data on all known bat reservoirs and camel breeding data. A predictive computer model shows the risk of MERS being transmitted into humans to be highest not in Saudi Arabia,

but in the horn of Africa, where most camels are produced. Therefore, this is where EcoHealth Alliance is now going to shift its focus, and again emphasized the inherent challenges of working within some countries in that region. Those places where the infrastructure and stability are gone, Daszak noted, and where animal migration is uncontrolled, are where we should be most concerned about a virus like MERS. It may be quietly spilling into the human population, becoming more prevalent in camels, and materializing to a real pandemic concern before we can become aware of it.

Assessing Viral Diversity

Many groups are doing viral discovery in wildlife, Daszak said. The challenge is to rank the viruses for follow-up genetic and experimental studies to assess further potential for spillover to humans. Ranking the risk for zoonotic potential of novel viruses is done based on virus-independent and virus-specific traits (see Figure 6-1). Even with these studies and the availability of modeling technology, Daszak cautioned that there is a tendency in the interepidemic period to reduce resources and allocate them elsewhere, showing a lack of priority and a long-term vision.

FIGURE 6-1 Ranking risk for zoonotic potential of novel viruses.
SOURCE: Daszak presentation, March 27, 2015.

RESPONSE TO THE 2003 SARS OUTBREAK

In November 2002, SARS emerged in Southeast Asia and quickly spread, aided by superspreader events, to become a global pandemic. Most of the cases were household contacts of those infected and health care workers. Frederick Cassels, chief of the Enteric and Hepatic Disease Branch of the Division of Microbiology and Infectious Diseases (DMID) at NIAID, noted that onset of fever was a very important symptom in the pretransmission phase, and isolating people with fever was a key intervention to control the spread, curbing the epidemic by April 2004.

NIAID/DMID Response: Contracts, Research,
and Grants

Cassels explained that NIAID has a dual mandate on both the basic and applied research side and on the rapid response side of the spectrum. In addition to a host of different grant mechanisms, NIAID provides support across the product development pipeline through resource facilities, partnerships, contract resources, and clinical trial support (generally through Phase II). The NIAID response to SARS included contracts, intramural research, and grants. The initial mechanism in 2003 was to rapidly supplement existing coronavirus grants. In 2004, approximately $100 million in SARS-specific grant funding was awarded. Contracts were established quickly, including three vaccine development contracts and a monoclonal antibody contract; however, funding was provided for only 4 years. Cassels added that the risk–benefit ratio changes over the course of an outbreak. When there are many cases, the risk is much higher. As the number of cases decreases, interest in finding a vaccine starts to wane, as others have highlighted, and the risk/benefit ratio changes, making a vaccine a “harder sell” from a regulatory perspective—among others.

Commercial SARS Vaccine Development

An important consideration is not only the dynamic nature of infectious disease threats but also the dynamic nature of the industry on which we depend to develop these vaccines, said Mansoura of Novartis. She briefly described a SARS vaccine development program on behalf of Jeffrey Ulmer, global head of External Research at GSK Vaccines, who worked on the SARS vaccine while at Chiron in 2003. The scientific

assumption being tested was that neutralization antibodies against SARS coronavirus would mediate protection, Mansoura explained.

An important note is that Chiron initiated and funded this program at their own financial risk when they saw the emergence of the outbreak in Hong Kong and Southeast Asia in 2002–2003, Mansoura said. Also important was the fact that researchers at Chiron had an ongoing collaboration with the University of Marburg Biohazard Level-4 facility, which enabled them to begin work immediately. Unfortunately, Mansoura said, the program ended in August 2009 due to expiration of the NIH grant and disappearance of the threat. In a large company like Novartis or GSK, opportunity costs drive decisions. If GSK is developing a SARS vaccine, they are taking resources away from developing the next-generation influenza vaccine. Therefore, if external funding disappears, it is unlikely the company will continue a program using only internal funds.

Mansoura summarized several of the success factors of the Chiron program:

1. Established access to containment facilities enabled the rapid sequencing and identification of the pathogen.
2. Preexisting insight into pathogen biology guided rational approaches to vaccine discovery and development.
3. External funding facilitated vaccine development.

A key limitation was the disappearance of the threat, which resulted in the lack of will to pursue this vaccine development program further. Another limitation was that traditional vaccine technologies are not amenable to rapid response, stressing the need for platform technologies. Arguably, she concluded, a decade of coronavirus vaccine development has been lost, and said it is time to ask the hard questions about what the cost of that inaction could be, before the consequences are seen.

Small Biotechnology Company Platforms Targeting Emerging
Infectious Diseases

Michael Wong, senior medical director for Infectious Diseases at Sarepta Therapeutics¹ shared his perspective on some of the challenges

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¹The statements made are Wong’s personal observations and are not made on behalf of Sarepta Therapeutics.

for a small-scale biotechnology company participating in the MCM enterprise.

Early work on SARS coronavirus identified several potential targets, Wong noted, and a lead-candidate therapeutic agent moved rapidly through animal studies to IND submission. Unfortunately, at that point, the epidemic had waned and the funding disappeared. Much was learned in the process, but none of that knowledge or data has been applied to looking into MERS or other emerging viruses because of limitations in the ability to be flexible within the context of a small biotechnology company.

Challenges for Small Companies

Wong described some of the issues from a commercial standpoint for a small company, including scale-up, funding, regulatory harmonization, and timelines. The economics of scaling up from synthesis and research, or small clinical study to production, is unfortunately not commercially feasible for MCMs that do not have some commercial output, he said. Smaller companies just do not have the resources to do this unless they are collaborating with federal agencies or co-marketing with other companies in the private sector. Downstream organizations, such as commercial manufacturing organizations that smaller companies contract with, also need to scale up. If they cannot, then the innovator is not capable of scaling up. Similarly, if downstream companies cannot meet timelines, this impacts the innovator’s timelines.

Another challenge for small companies is that bridge funding stops at certain points, leaving gaps in funding that impede progress in development. Regulatory and trade issues of bringing investigational agents into other countries continue to exist as well. Wong also mentioned the difficulty in articulating to countries and populations the need to ensure the safety and efficacy of a product, and a real-life, on-the-ground need to respond in an emergency—previously alluded to regarding clinical trials during the EVD outbreak. “We need to keep the dialogue going about how this is done within developmental, legal, and ethical frameworks so that we are ready to respond correctly,” he said. Finally, he concurred with others that the appropriate infrastructure needs to be in place for countries or organizations to be ready to accept the type of support or aid that industry is attempting to contribute.

SUSTAINING PRODUCT DEVELOPMENT

Themes throughout the presentations included the missed opportunities for coronavirus research after both the threats and funding decreased, and the potential urgent need to reinstate vaccine candidate development programs within a short timeline, Inglesby of the Center for Health Security said. Panelists discussed what would be needed to sustain a viable coronavirus vaccine development program in the absence of an outbreak. The focus would need to be defined, said Cassels of NIAID. Would such a program be SARS-specific, MERS-specific, or pan-coronavirus? Universal influenza vaccine efforts have arisen from decades of research to identify potentially universal strategies, yet there is still a long way to go and the coronavirus field is not yet ready for that, Cassels stated. Daszak agreed that developing pan-coronavirus platforms will be very difficult. However, viral discovery suggests that there will be many other coronaviruses that are close to MERS or SARS that may use the same receptor, or a different receptor that could be covered by a MERS or SARS vaccine. Wong also called for the need for dedicating resources toward coronavirus therapeutics discovery and development in addition to vaccines.

Sustainability depends on the mission and the direction of the company, Wong continued, saying the will and vision of a strong leader can move a company, but it also requires the company to have the resources to sustain the process. A company must consider the value or return on investment of the program. For smaller companies, value plays a much larger role in making strategic decisions to move forward or to suspend a program. Wong also reiterated that his company has done many proof-of-concept studies with Sarepta’s phosphorodiamidate morpholino oligomer (PMO) platform, but only the filovirus program is progressing because it is the current hot topic and some limited funding is available. Waiting for a virus to emerge to move platforms forward in development will not be a sustainable way to achieve progress.

Mansoura reiterated the point made by Venkayya of Takeda and others that corporate social responsibility alone will not drive a company to develop a product. Partnerships and the approaches to reduce the risk for companies are needed. One of the challenges for government funders is allocating the right amount of money to draw in the types of partners needed. Government partners also face challenges in ensuring the size of the market. The days of multibillion dollar, multiyear budgets are gone, she said, and agencies are limited to working with annual appropriations

that are subject to change each year. Inglesby added that it would be useful to have a sense of the funding needed to develop a final licensed product targeting a coronavirus. Additionally, a separate, lower number, that shows the amount of funding needed to develop a product to a certain endpoint is needed, for example, a Phase III–ready asset. Pavia of the University of Utah stressed the need to engage more experts in business, economics, and even behavior to understand how to sustain momentum in funding and support when the need is not clearly present. Participants also highlighted an opportunity for more innovative ways to secure funding. We should not always be looking to the government, Cox said. Compelling stories are needed to interest investors, and we need to learn how to better engage potential stakeholders that have an interest in finding a solution.

Lack of Public Understanding of Threats

Investors are interested at the height of a crisis, Daszak said. He pointed out that the share value for Roche Holding, a Swiss global health care company, increased during the H1N1 influenza pandemic. Unfortunately, as discussed, the interest and hype are short lived and focused around the outbreak. Daszak shared a story of a publication in Nature describing SARS in China and work done with colleagues from China’s government-funded laboratory. The publication garnered no interest from the Chinese government, he said, and no one they talked with from the live animal markets seemed concerned about the findings. What was surprising for Daszak was how little interest was shown in the article from outside governments and the general public. Based on his experience and understanding, significant attention and interest should have come out of that article, but instead only a few virologists were interested in the paper for academic purposes—again showing the strong influence the media can have on public perception of threats.

Daszak also shared that during the recent Ebola outbreak, EcoHealth Alliance issued a press release and an analysis predicting which countries would be the first to be infected as a result of global air travel.² The United States was predicted to be one of the top three countries that would receive infected individuals from countries with EVD, and it was predicted the patient would arrive into Dulles, Boston Logan, Newark, and/or JFK airport. They anticipated a lot of attention and coverage, but

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²See http://www.ecohealthalliance.org/press/101-ecohealthallianceidentifiesebolasflightpathtotheus (accessed September 30, 2015).

instead, again, there was very minimal pickup by the media. Daszak reiterated that, until an infectious disease crisis is very real, present, and at an emergency threshold, it is often largely ignored. To sustain the funding base beyond the crisis, he said, we need to increase public understanding of the need for MCMs such as a pan-influenza or pan-coronavirus vaccine. A key driver is the media, and the economics follow the hype. We need to use that hype to our advantage to get to the real issues. Investors will respond if they see profit at the end of process, Daszak stated.

Prioritizing Investment

At the workshop there was broad recognition that many threats exist, with only limited financial resources to address these threats. Hundreds of thousands of viruses exist, and it is impossible to prepare for all of them, Swerdlow of CDC said. A participant summarized that “we are either paralyzed to inaction because there are too many threats and we don’t know where to start, or we are busy dealing with the threat of the moment.” Pavia added that we need to consider how prepared is prepared enough: What basic science is needed; what regulatory reforms are required; what stage of development should products be taken to; and what platform-based technologies are needed to fulfill an even cost–benefit ratio? However, he acknowledged that if the funding to answer these questions is not available, if the FDA does not work on regulatory pathways, if partnerships cannot be established in the interepidemic period, none of these things will happen at the rate that a response demands.

Incorporating Holistic Assessments and Transparent Needs

Prioritization and transparency are pragmatic keys to moving forward. Participants discussed the feasibility of an IRAT-like tool that could prioritize across threats that are not yet at crisis level. Richard Hatchett, chief medical officer and deputy director at BARDA, noted that BARDA is working on this type of assessment tool. He also emphasized the importance of a holistic assessment, considering not only the biological properties of viruses and hosts but also the social and behavioral contexts in which a disease could emerge to become a crisis. Certain categories of threat would be clearly prioritized (e.g., organisms capable of respiratory transmission; highly lethal viruses, such as hemor-

rhagic fevers, that will be disruptive with just a few cases). Daszak concurred about the importance of considering the social context. He noted that EcoHealth Alliance does behavioral risk characterization in all of the countries in which it works, interviewing people most at risk to get a sense of how they are connected to the wildlife and where potential spillover incidents could occur. He suggested that the percentage of the gross domestic product spent on health care is also a predictive factor to consider (impacting the ability to report and to manage a disease), as are issues of governance and political corruption (impacting the willingness to report and respond to international authorities).

Mansoura of Novartis said it is informative to look at previous prioritization efforts and their outcomes. For example, there have been six agents on NIAID’s Category A priority pathogens list, including Ebola, since it was created in 2002. Yet, nearly 15 years later, there was not an Ebola vaccine available during the outbreak. The 2012 PHEMCE strategy document gave very ambiguous signals about whether or not an Ebola vaccine was a priority. Conversely though, the private sector looks at those reports very closely to guide their work, she said. Transparency and a clear signal are important. Courage and political will are needed to sustain these investments, she argued, and we are not even asking for a fraction of what we need.

Daszak of EcoHealth Alliance said it is important to be working for the long term on products such as a pan-coronavirus vaccine platform and working on an animal vaccine, but near-term public health control measures, such as changing behavioral risks, increasing infection control in hospitals, are just as critical. Despite the analysis of travel patterns showing a clear risk that people with EVD would arrive in the United States, airports were very slow to enact the simple measure of screening the temperature of arriving passengers, Daszak said. While MCM development is a key piece of the response puzzle, Osterholm of CIDRAP highlighted the need for stronger human and animal surveillance to help guide industry actions and public health interventions together.

ANIMAL VACCINES

Several participants discussed options of potentially preventing outbreaks through vaccination of animal sources, specifically, developing a MERS vaccine for camels. Osterholm suggested that a camel vaccine

could be developed and approved much more quickly than a human vaccine, and could help to lower the risk of further spread.

Daszak concurred that the current human exposure to MERS is clearly through camels. He added that Australia also has a large population of camels, but MERS has not been identified in that population. Although there is a market for a camel vaccine, he believed the potential for funding such a vaccine was limited because the immediate focus is on addressing human disease. He suggested that perhaps the Saudi government and others could be persuaded to commit resources to a camel vaccine, but recalling Kumar’s statements from Chapter 3, these issues should not be left for individual governments to solve alone. Swerdlow mentioned that there has been discussion about camel vaccines during reviews of the PHEMCE portfolio, and it was also his understanding that the Saudi government was working with some companies on this issue. With the One Health concept encouraging more and more interaction between human and animal health experts, continued discussion could promote multidisciplinary approaches to solving the same problem—in this case, eradicating a human disease transmitted by animal populations.

Chapter 6 Annex

This annex contains technical details from the
speakers’ presentations related to the development of
products targeting coronaviruses.

David Swerdlow

Associate Director for Science, National Center for Immunization and
Respiratory Diseases, CDC

In 2012–2013, ASPR, BARDA, and CDC collaborated to create a coronavirus risk assessment tool based on IRAT, Swerdlow said. As discussed by Katz in Chapter 5, IRAT uses information about novel influenza virus isolates (virus properties, population properties, viral ecology) to assess the risk of emergence and the potential public health impact if the virus does emerge. Risk elements from IRAT were reviewed for relevance to MERS-CoV and categorized as most important for coronaviruses (disease severity), very important (human infections,

global distribution, infection in animals, antiviral treatment options), or important (antigenic relationship, genomic variation). Several IRAT elements were not at all relevant to coronaviruses or could not be assessed with available data (population immunity, receptor binding, transmission in animal models), which made it difficult to gain a true assessment of MERS-CoV.

Peter Daszak

President, Ecohealth Alliance

Daszak and colleagues also sought to understand the extent of viral diversity in mammals. A fruit bat species was repeatedly sampled for the occurrence of 55 viruses from 9 viral families. Using statistical methods to estimate the total unknown diversity of viruses from that species, they estimate 58 unknown viruses in that bat species, and extrapolate about 320,000 unknown viruses in all mammals, including about 72,000 in known bat species (Anthony et al., 2013). The cost to identify 100 percent of these unknown viruses is estimated to be $6.8 billion. Because it is an exponential curve, cost to identify 85 percent is estimated to be $1.4 billion. While that seems like a large amount, for comparison, Daszak stated that the cost of responding to SARS was $10–$50 billion for a single outbreak. The cost of the current EVD outbreak response is estimated to be $32 billion. However, as noted throughout this report, funding is difficult to procure until the country is in “response mode.”

Put simply, emerging infectious diseases are increasing over time and there is an unknown diversity of potential pathogens. He noted that the rate of discovery of bat viruses has increased significantly in the past 5 years, but only 7 percent of the total estimated viruses are known. Modeling hot spots for emerging diseases, though, can be used to target surveillance and resources more effectively (Jones et al., 2008). Daszak pointed out that West Africa was identified as a hot spot in 2008, and, although they approached USAID to fund the study of wildlife reservoirs in the area, no resources were available at the time.

Michael Wong

Senior Medical Director in Infectious Disease, Sarepta Therapeutics

The company has about 300 employees across three campuses, and although the company’s primary vision is addressing a neuromuscular disease (Duchenne muscular dystrophy), Sarepta is now assessing the use

of this technology in the anti-infective arena. The proof of concept for infectious diseases had been performed in vitro in more than 21 viral families, including filoviruses (Ebola, Marburg), coronaviruses (SARS), and pandemic influenza. Wong noted that therapeutic candidates for Ebola, Marburg, and pandemic influenza have gone through animal efficacy and Phase I human safety and pharmacokinetic studies. He added that much of the work is being done with company funding that is from investors/stockholders, at their own risk.

Michael Osterholm

Director, Center for Infectious Disease Research and Policy (CIDRAP)

Osterholm noted that, while culling civets in the markets in Southern China helped to control the SARS outbreak, there has been no similar success in controlling human exposure to animal carriers of MERS mainly because of the social implications of camels. The camel population is huge, he said, and they are integral to the life and culture of people in the Middle East. He said there are 1.5 million dromedary camels in the Arabian peninsula, and 10.5 million in the horn of Africa through Northern Africa, and there is increasing trade of camels between the Arabian peninsula and Africa. MERS in camels will likely spread throughout the region, including to terrorist-controlled areas where there is limited infrastructure, increasing potential for human exposure.

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