Preparing for Disease X in a Changing World

COVID-19 took the world by storm in early 2020, being declared a pandemic in March of that year. While it was the most recent emerging infectious disease, experts anticipate it won’t be the last. Well before COVID-19, scientists have been prepping for emergence of an unforeseen pandemic: a Disease X (also called pathogen X).¹ In 2018, WHO first introduced the term Disease X, described as “an unknown pathogen that could cause a serious international epidemic.”

“Pathogen X could be anything, including a pathogen that we already have that just mutates in a way that we have never thought about, and instantly becomes a monster,” said Kariuki Njenga, a virologist at Washington State University (WSU), explores emerging and re-emerging infectious diseases. “Or it could be something that we have never seen before, like SARS-CoV-2.” The question is: When this pathogen emerges, will researchers, and the world, be ready?

Known Pathogens Offer Clues for Disease X

Working full time in Kenya as part of a non-government organization, WSU Global Health-Kenya, which promotes public health and related research in the region, Njenga studies how viruses that cause diseases like Ebola, Rift Valley Fever (RVF), and Middle East Respiratory Syndrome (MERS) are transmitted and maintained in the environment. “My wife always teases me and says, ‘when there's a dangerous disease, people are running away, [but] you are going there, so you’re such a weird person’,” he said.

Having worked in the field for several decades, Njenga has seen the state of emerging infectious diseases change. “More recently I've seen many more emerging pathogens than we had ever seen before,” he said.

One of the ways that scientists like Njenga tackle the question of pandemic preparedness is by studying known pathogens. These familiar microbial threats have the potential to mutate, becoming more transmissible or acquiring new features that increase their severity. They can also serve as models for future similar, but new, pathogens.

Njenga’s group studies transmission and disease dynamics of MERS, a coronavirus that emerged in 2012.² Researchers found that camels served as the main reservoir for this host, with human transmission predominantly only occurring in hospital settings.^3,4 However, MERS infections in the Middle East and Asia had a lethality rate of 35 percent. In contrast, the strain circulating in Africa has not caused severe disease to date in humans, despite the fact that the virus is abundantly present in domestic camels throughout the region.^5,6

The rare cases reported in Africa have been from asymptomatic individuals, but because previous studies demonstrated evolution in other MERS strains, Njenga’s team actively surveils the virus’s genome to track possible genomic changes that may enhance the camel-to-human or human-to-human transmission.^7,8 “Could this virus be changing genetically and, one of these days, [are we] going to have COVID 2.0 kind of disease from this particular virus?” he posited. Additionally, Njenga’s team is studying genomic differences in MERS strains to understand this distinction in disease severity.

Njenga also explores the factors behind varying disease severity and survival in patients following Ebola infections. Although this virus is unlikely to reach pandemic levels, Njenga said understanding these different immune responses can provide insights into new therapies. “We go in there and we ask, ‘what can we learn from these to be able to respond better and to be better prepared?’,” he said.

Thomas Geisbert, a virologist at the University of Texas Medical Branch at Galveston, asks similar questions in his research involving emerging infectious diseases. Geisbert attributed his interest in some of the world’s most dangerous known viruses to his curiosity. “I just always thought that was intriguing to work with viruses that were that deadly and try to come up with ways to stop them,” he said

Preparing for Disease X Takes a Multipronged Approach Pathogen discovery, risk assessment, and novel therapeutic development help researchers prepare for the next microbial threat. As humans continue to alter landscapes and face more wildlife interactions, the risks of a new infectious disease emerging increase. To prepare for the unknown Disease X, researchers are studying the composition of pathogens circulating in wildlife, monitoring changes in activities and environments that increase the risk of pathogen spillover into humans, and developing therapeutic interventions that could potentially be rapidly deployed. 1) Traditionally, researchers identified new pathogens after they crossed over and caused disease in humans or other animals. One plan to get ahead of these emerging diseases is to better understand what microbes are already present in nature, but characterizing these pathogen burdens can be complicated because of physical constraints in collecting samples. Advances in diagnostic technologies and novel methodologies are expanding researchers’ abilities to profile known and unknown pathogens in wildlife. a) To overcome limitations in sample collections from larger animals, scientists developed non-invasive techniques to use saliva from discarded food to detect known and possibly unknown pathogens using PCR. b) Meanwhile, improvements in multiplex assays expand the use of serology for large and small animals, where samples like blood are limited, to learn what these animals may have been previously exposed to. 2) Factors like climate change, altered land use, and human migration are changing what animals people encounter, but the impact of these changes remains unclear. Scientists are using modeling and household and wildlife surveys to study how changes to environments and behaviors are affecting what animals are present in an ecosystem and how humans are interacting with them. They can use this data to determine what practices pose the greatest risk to disease exposure. Researchers then hope to use this information to determine how to mitigate this risk. 3) Scientists don't know what exact virus may be the next to cause an epidemic or pandemic. However, by developing vaccines and therapies like antivirals and monoclonal antibodies against highly shared elements of known pathogens, researchers can have platforms ready to quickly design interventions against a similar virus that causes an outbreak.

This interest led him to studying Ebola in the early 2000s. In 2005, Geisbert and his colleague Heinz Feldmann developed a recombinant viral vector Ebola vaccine that fully protected monkeys.⁹ However, for pathogens like Ebola, which cause sporadic outbreaks but don’t reach the level of a pandemic, Geisbert said that getting funding and commercial support to advance these therapies is difficult. “This has been so frustrating for me for my whole career,” Geisbert said.

“That vaccine just sat there for years and years and years and years, and we knew it was good,” he added. “Sadly, it took that Ebola epidemic in West Africa in [2014-2015] to get that thing across the finish line, for somebody to show an interest in [it].”

In response to this shortcoming, international governments and charity foundations created the Coalition for Epidemic Preparedness Innovations (CEPI) to support the development and testing of vaccines and other interventions for emerging infectious diseases.

Geisbert said that this is a good change that can help move therapies forward for diseases that affect smaller populations. However, he pointed out that any outbreak can wind up having widescale implications, adding, “Who thought that COVID would take off like it did?”

Follow the Food: New Pathogen Discovery Approaches Aid Disease X Prep

Scientists may not be able to predict when a spillover will occur or which pathogen may become Disease X, but having a better grasp of potential candidates can help inform researchers of what to expect and prepare for.

Tierra Smiley Evans, an infectious disease epidemiologist at the University of California, Berkeley studies the viruses that circulate in wildlife species, in particular mountain gorillas and bats. She is also the chief veterinary and scientific officer for Gorilla Doctors, a nonprofit organization that provides medical care to gorillas in Uganda, Rwanda, and the Democratic Republic of Congo and conducts research to advance animal health.

As a wildlife veterinarian, conservation, especially of endangered primates like mountain gorillas, is important to Smiley Evans. “Nonhuman primates are a really important part of the ecosystem,” she said, explaining that these animals are susceptible to the same infections as humans, posing a risk for outbreaks that occur in one species to be shared with the other. Although primates are not the reservoirs of viruses, they can act as bridges between the wildlife that harbor these pathogens and humans.

“It's really important to study these viruses at this particular interface where humans are moving closer into wildlife habitats that they haven't contacted before,” Smiley Evans added. “That's where we could potentially do the most benefit, because that's where we can catch things before they spill over and become a big issue.”

However, anesthetizing large wild animals for sample collections is difficult, dangerous, and, for endangered species like mountain gorillas, potentially not permitted. For noninvasive testing, Smiley Evans and her team developed a method to detect viral nucleic acid from saliva on discarded plant material that the animals have eaten; this approach is much easier than tracking feces, as—similar to some of their human cousins—these animals snack often.¹⁰ By looking at conserved regions across a viral genome, the team can use PCR to detect both known and possibly novel viruses in these animals. “That being said,” Smiley Evans added, “detecting a PCR-positive sample in a nonhuman primate is like looking for a needle in a haystack.” This is because most of these animals are healthy.

To overcome this obstacle, her team is exploring using this method to detect antibodies in animal saliva, which can tell the researchers what the animals have been exposed to. Coupled with more multiplex assays, the researchers can test for multiple pathogens from the same sample. “[It’s] allowing us to look at primate populations in a whole different way and really tying them to the landscape,” she said.

These multiplex serology platforms are also improving her team’s ability to study exposures in bat species, which are known to harbor many viruses. “A lot of times we work with really, really tiny species,” Smiley Evans said. Traditional enzyme-linked immunosorbent assays (ELISAs) require large amounts of blood samples, but in the researchers’ bats, they could only collect a drop or two. With multiplex platforms, they can now test for 20–30 pathogens with just five microliters of blood, increasing their ability to profile these animals’ pathogen burdens.

We simply don't know enough about the origins of these pathogens.

—Kris Murray, London School of Hygiene and Tropical Medicine

This profiling allows Smiley Evans and her team to identify any new pathogens circulating in animal communities, giving them a leg up in preparing for potential human exposures. Additionally, profiling communities of people in high contact with animals, like bats, demonstrates what viruses are already capable of infecting humans.¹¹ The group also investigates pathogens responsible for infectious diseases in communities near these forests to try to identify spillovers.¹² “Making sure that we're addressing both sides of the wall, so to speak, is the only way that effective conservation can work,” she said.

However, for both Smiley Evans and Njenga, the field sites are anywhere from six to 15 hours away from the nearest research laboratory that will process their samples, introducing unique challenges. “[It’s] hard to keep cold chain when you're doing sampling and making sure your samples, that take so much time and effort to collect, are properly preserved,” Smiley Evans said. Supply chain issues introduce hurdles as well. “Sometimes getting all of the reagents that we want for our tests is not always straightforward and easy.”

Additionally, despite the recent explosion of genomic technologies in other parts of the world, Njenga explained that many of these remain out of reach for many low- and middle-income countries. “We really struggle with getting enough diagnostic and genomic tools in these areas to be able to do the work in real time,” he said. Improving access to these tools and genomic resources could improve not only pathogen discovery efforts but also responses to known pathogens, such as evaluating if a patient should be isolated.

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Microbiology

Viral Research Gets Batty to Study Spillovers

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How Human Activities Could Drive Disease X Outbreak

Beyond tracking pathogens, researchers are interested in how people encounter pathogens and what actions may increase these risks. Kris Murray, an ecologist at the London School of Hygiene and Tropical Medicine, studies how land use changes in The Gambia impact interactions between humans and animals and, in turn, their risk for pathogen spillovers. According to him, one lesson that became obvious following COVID-19 was that scientists aren’t prepared enough to handle the next large outbreak. “We simply don't know enough about the origins of these pathogens,” Murray said. “We don't know enough about the ecology of the way that they move from their hosts into the human population.”

Human activities influence the risk of spillovers by bringing people closer to wildlife and their habitats and increasing their exposure to novel pathogens.¹³ For example, Murray’s group previously demonstrated how land use changes, such as deforestation for agriculture, increased malaria risk in sub-Saharan Africa.¹⁴ Additionally, they showed that these disturbances shifted the diversity in bat species, which led to an increase in viral abundance in remaining animals.¹⁵

However, “There's a bit of a gap in this particular component around human animal contact,” Murray said. Currently, most surveillance identifies a pathogen in an animal or a human. “The bit that's missing in all of that for us is that very central process of human-animal contact and whether that itself is predictive of the human infection patterns that we're seeing.”

To address this, Murray’s group is interviewing households in the Central River Region of The Gambia about their animal contact and collecting blood samples from humans and domestic and wild animals to compare pathogen burdens and exposures. “Our plan is really to try to map that sharing network of pathogens and then link that to the human animal contact patterns and look at the role of land use in shaping that sort of dynamic network.”

Even if you come up with a treatment or a vaccine that saves one person's life, it's worth it.

—Thomas Geibsert, University of Texas Medical Branch

For these studies, they partnered with colleagues in Nigeria conducting similar investigations. Working with anthropologists, the researchers also hope to be able to compare how cultural differences influence exposure risks. Understanding how these contacts and the activities that lead to them influence pathogen risk can help inform scientists and communities to prepare for or reduce outbreaks.

Smiley Evans also considers how conservation and health recommendations scientists like herself make impact the livelihoods of these communities.¹⁶ “We have to always come in with the perspective that our goal is to help both sides and to make both sides flourish, and that has to be communicated effectively.”

Njenga said that the Global Health program at WSU helps promote this communication by hiring researchers that are native to these geographies. He explained that since he looks like the members of these communities and speaks the local language people are more comfortable talking to him. “It's working really well in terms of allowing us to be able to do studies and engage people,” he said. “Also, when you want to study the socio-cultural factors that interfere or impact transmission of disease or control of it, then it becomes a lot easier because we have this rapport that we have established in these communities working with them for a long time.”

Climate Change Shifts Disease X Risks

Another factor in the shifting risk of emerging pathogens and Disease X is the role of climate change. “There’s no question that climate change is having an impact on the spread of infectious diseases and the populations of wildlife and where they can live and where they can move,” Smiley Evans said.

She explained that 15 years ago she and her team didn’t need mosquito nets or antimalaria medications because the temperature was too cold. Now, she said, “It’s just so strikingly different.”

To study these changes, her group traps mosquitoes across their research field sites and throughout the seasons and samples their virus profile by PCR, assessing both the number of mosquitoes as well as the variety of species. Meanwhile, in another project, the team compares serum from wildlife collected decades ago to that of animals in the same geographic regions today to see how the virus profiles have shifted. “It's going to be interesting to see what's happening as [climate change is] accelerating even more in the coming decades.”

However, climate change-induced migration shifts in mosquitoes and other animals are already changing disease risk in known pathogens. Murray’s team used modeling to explore how climate change-driven weather alterations increased genetic diversity and infection dynamics of a fungal pathogen in amphibians, contributed to cholera outbreaks, and influenced the development of mosquitoes in different geographic regions.^17-21 These predictions can be important tools in anticipating disease risk in new areas.

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Genetics

Mosquitoes Adapt to a Warming Environment

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For example, Njenga’s team used modeling and epidemiological data to show that, due to climate change altering weather patterns in Africa, RVF has reached brand new geographies.²² “That perhaps suggests that if you have the right environmental conditions or climatic conditions, now we have the virus everywhere, and you could get an explosive outbreak,” he said.

To address this concern, Njenga and his team are exploring how climate change is shifting mosquito populations. Additionally, they are exploring whether and how RVF virus itself is evolving as temperatures change.²

Pathogen Prototypes Help Prep for Disease X

Profiling wildlife pathogens and identifying risky behaviors are two arms of a three-pronged approach to preparedness. Even with all of the knowledge on virus diversity and spillover risks, outbreaks will still happen. Having vaccines and interventions ready to be produced and distributed can lessen the impact of the next pathogen emergence.

Following COVID-19, the National Institutes of Health launched the Research and Development of Vaccines and Monoclonal Antibodies for Pandemic Preparedness (ReVAMPP) network. This initiative funds research into vaccines and monoclonal antibodies targeted against a specific family of viruses, using a known pathogen as a prototype to develop from.

“It's kind of developing strategies based on a family of viruses and hoping that that can be translated, you know, if something new pops up,” Geisbert explained. His team, through ReVAMPP network funding, use Nipah viruses as their prototype pathogen for vaccine development.

Over his decades developing vaccines and therapies for these viruses, Geisbert has seen his fair share of failures. “It’s really, really frustrating,” he admitted. However, he found that learning what doesn’t work has led him and others to strategies that worked. One example is his group’s viral vector-based vaccine that they originally developed against Ebola and, seeing its success, applied that platform to other viruses, including Nipah virus.²⁴ “Even if you come up with a treatment or a vaccine that saves one person's life, it's worth it,” Geisbert said.

Aside from preventative vaccines, Geisbert and his team are also exploring oral antiviral treatments that can improve containment strategies in the early stages of an outbreak. Their drug, obeldesivir, protected infected monkeys against the Ebola disease when it was given one day after viral exposure.²⁵ “A lot of times you're going to stamp it out that way, because you're breaking the chain of transmission if you have those kinds of treatments.”

Defense Against Disease X: Are We There Yet?

“Are we better prepared now that we went through COVID to be able to handle the next pandemic?” Njenga mused. “The answer is yes and a small no.” The speed at which SARS-CoV-2 was sequenced and made available, followed by the rapid development of vaccines demonstrated the capacity of the research community to respond quickly. These advancements reinvigorated interest among funding agencies to support universal vaccine development and treatment options. “In that sense, I think we are better prepared to be able to respond,” Njenga said.

However, he finds that anxiety about pathogen discovery research, based on fears that researchers exploring wildlife pathogens will lead to a new agent being introduced to the general population, interferes with this preparation. Between humans increasingly invading spaces previously only occupied by wildlife and more global interaction, like tourism, people will inevitably be introduced to new pathogens. “If we don't go there to study them,” Njenga explained. “They'll find us unprepared because people are going to go there and get infected and get them.”

Instead, by learning what is circulating in the natural world just on the other side of human communities and by studying how our interactions and activities may expose us to these pathogens, researchers can be prepared to tackle this threat, whenever it arises.