At any given time, countless viruses and bacteria are being spread around the globe, often evolving quickly as they move. In some cases, the explosion of a new disease is stopped short of becoming a pandemic by quick-acting public health authorities; in other cases long-term research offers vaccination or eradication solutions at just the right moment. But sometimes, a pathogen gets the upper hand.
“The number of outbreaks that occur and are reported to the World Health Organization (WHO) each year is amazing,” said Suerie Moon, MPH, PhD, research director and co-chair of the Forum on Global Governance for Health at the Harvard Global Health Institute in Cambridge, Massachusetts. “It is in the range of 200 to 300 per year.”
Some are small, affecting a handful of people. Others reach pandemic proportions. Now, the threat of mosquito-borne Zika virus is looming over the Americas. “It takes time to study these things,” said Paul Roepe, PhD, a professor in the department of chemistry at Georgetown University and co-director of the Georgetown Center for Infectious Disease in Washington, D.C. “You can snap your fingers and launch an immediate response. But if you really want to be able to respond to a disease like Zika in a timely, educated way, you would have been studying it ten years ago.”
With new tools at their disposal, researchers are learning about pathogens more quickly. But even better tools and more funding are needed, Roepe and others argue, while also cautioning that predicting the next pandemic is no exact science.
Preparing for Zika
Zika, a flavivirus transmitted by mosquitoes, is far from new—as is the case with most pathogens that lead to pandemics. The virus was discovered in Uganda in 1947 and, through the following decades, caused scattered instances of mild illness in Africa and Asia. Things changed, though, when the first cases arose in South America in 2015. Cases of a rare neurological complication, known as Guillain-Barré syndrome, as well as babies born with microcephaly, were reported in association with the disease. By February 2016, Zika was spreading rapidly throughout the Americas, and WHO had declared a public health emergency.
In a matter of months, scientists from around the world sequenced the genome of the latest Zika strain, crystallized the protein components of the virus to elucidate their structure, developed mouse and primate models of Zika infection, and developed a rapid RNA test to detect the virus. “The information is changing incredibly rapidly right now,” said Jane Hata, PhD, director of the clinical microbiology laboratory at Mayo Clinic Florida in Jacksonville. That’s both because of the pace of research, and because a virus like Zika changes and mutates as it spreads.
As of early June 2016, all Zika cases in the U.S. originated from travel to countries where the virus was endemic or through intimate contact with individuals who had visited affected areas. But officials at the Centers for Disease Control and Prevention (CDC) are already bracing for the day when Zika is actively transmitted in the U.S. They have been encouraging aggressive testing for Zika among pregnant women who have traveled to Central or South America or who live in the southern states where Zika-carrying mosquitoes could be found. “Florida has been triaging these cases very vigorously,” Hata said. “Any pregnant woman who has been to an area where there’s active Zika transmission is being asked to get tested, whether or not she is symptomatic.”
Of course, a trip to South America shouldn’t necessarily trigger diagnostic testing for Zika. “The bottom line is that not everybody needs to be tested,” Hata said. An estimated 80% of people with Zika virus are asymptomatic and in most, there is no risk of long-term complications, she added. But when women are infected early in pregnancy, they put their fetus at risk of developmental abnormalities, so testing is key for individuals trying to get pregnant or who are already pregnant.
As research on Zika continues, testing protocols—until recently, all being carried out at CDC and state laboratories—are changing. Initially, CDC was using real-time reverse transcription–polymerase chain reaction (rRT-PCR) tests of blood samples to detect viral RNA. But the tests could only diagnose disease in the first week or so after onset of symptoms.
To help diagnose patients outside this window, the Food and Drug Administration (FDA) in February granted an emergency use authorization (EUA) for the CDC Zika IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA), which detects immunoglobulins from 4 to 5 days after the onset of symptoms until about 12 weeks later. But the ELISA has its own drawbacks; IgM tests for Zika are known to cross-react with other flaviviruses, including dengue fever and encephalitis.
“These three diseases can have really similar symptoms,” said Hata. “So a detailed history of where someone has been, and when, needs to be part of the differential diagnosis.”
In early May, CDC made a discovery that changed the agency’s testing protocols slightly: rRT-PCR could detect the virus for up to 14 days in urine samples. CDC officials immediately began recommending testing both blood and urine in patients in the 5- to 14-day window after the onset of symptoms. Then, in late May, to clear up the confusion that comes from false-positives, CDC issued new interim guidance recommending a plaque reduction neutralization test to confirm positive or unclear ELISA results. All three tests, however, take days to weeks for results.
In fact, getting diagnostic tests for rapidly disseminating infections from the point of regulatory approval to clinical use not uncommonly presents a speed bump for public health officials. This problem often rears its head during outbreaks, according to Hata. “On the scientific side, there can be lots of progress; new methodologies, new approaches to diagnosis,” she said. “But then the problem is getting those tests FDA-approved and commercialized. That’s where we can get hung up.”
It was not until late April that FDA granted EUA for the Quest Diagnostics Zika Virus RNA Qualitative Real-Time RT-PCR test (Zika RT-PCR test), which is available from certain Quest reference laboratories. Since then, FDA has granted EUAs for several test kits available to clinical laboratories, including, in May, the Altona Diagnostics GmbH RealStar Zika Virus RT-PCR Kit, and in June, Hologic’s Aptima Zika Virus assay. Both detect viral RNA.
FDA admits there is a long road on the way to having approved drugs for Zika, mostly because research is only beginning to ramp up. “It is important to keep in mind that for an emerging threat like the Zika virus, we are starting from almost stage zero with respect to vaccines and therapeutics,” said FDA press officer Tara Goodin. But she added that the agency is open to accelerated approval timelines. Already, on June 20, it approved a clinical trial for an experimental Zika vaccine.
Predicting the Next Pandemic
Scientists think hundreds of thousands of viruses are able to infect mammals, so how can they predict which ones are most likely to cause an epidemic and should be given priority in research programs? It will never be an exact science, Moon said. “There’s a long list of pathogens that merit attention by policymakers,” she said. “At the end of the day, though, it’s difficult to predict what will appear when and where. Zika is a great example of that.”
Genomics and computational biology are both helping make some predictions, though. “We can now sequence genomes in a matter of days and get an enormous amount of information about a new microbe very quickly,” Roepe noted. “That’s certainly helpful.” Sequencing platforms specially optimized for viruses—like VirCapSeq-VERT, which researchers unveiled in September 2015—use some 2 million probes to capture and sequence from a simple blood sample nearly every known human virus. While not yet commercialized, it is a step toward faster viral diagnosis—especially important when virus symptoms and ranges overlap, such as with Zika and dengue fever.
Experts each have their own choice of candidate pathogens poised to cause an outbreak. Generally, they name diseases that are already causing problems in some areas of the world—Roepe, for instance, pointed toward yellow fever, currently causing deaths in Angola; Moon named Middle East Respiratory Syndrome, which killed dozens last year in South Korea. And WHO has its own list—which includes both of these, as well as eight more emerging diseases.
Even without knowing which pathogen might cause the next global pandemic, policymakers, labs can prepare by having response plans in place. “I always recommend that labs think about specific scenarios,” said Hata. “What would you do, and how exactly would you do it, if a patient came in one afternoon and needed Zika or Ebola testing?”
Sarah C.P. Williams is a freelance writer who lives in San Antonio, Texas. Email: [email protected]