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Science Magazine: How many Ebola cases are there really?

Every couple of days, the World Health Organization (WHO) issues a “situation update” on the Ebola epidemic, with new numbers of cases and deaths for each of the affected countries. These numbers―9216 and 4555 respectively, according to Friday’s update―are instantly reported and tweeted around the world. They’re also quickly translated into ever-more frightening graphics by people who follow the epidemic closely, such as virologist Ian Mackay of the University of Queenslandin Brisbane, Australia, and Maia Majumder, a Ph.D. student at the Massachusetts Institute of Technology in Cambridge who visualizes the data on her website and publishes projections on HealthMap, an online information system for outbreaks.

But it’s widely known that the real situation is much worse than the numbers show because many cases don’t make it into the official statistics. Underreporting occurs in every disease outbreak anywhere, but keeping track of Ebola in Guinea, Liberia, and Sierra Leone has been particularly difficult. And the epidemic unfolds, underreporting appears to be getting worse. (“It’s a mess,” Mackay says.)

So what do the WHO numbers really mean—and how can researchers estimate the actual number of victims? Here are answers to some key questions.

Does WHO acknowledge that the numbers are too low?

Absolutely. In August, it said that the reported numbers “vastly underestimate” the epidemic’s magnitude. WHO’s situation updates frequently point out gaps in the data. The 8 October update, for instance, noted that there had been a fall in cases in Liberia the previous 3 weeks, but this was “unlikely to be genuine,” the report said. “Rather, it reflects a deterioration in the ability of overwhelmed responders to record accurate epidemiological data. It is clear from field reports and first responders that [Ebola] cases are being under-reported from several key locations, and laboratory data that have not yet been integrated into official estimates indicate an increase in the number of new cases in Liberia.”

Where do the reported numbers come from, and why are they always too low?

Officially, the governments of Guinea, Sierra Leone, and Liberia transmit the numbers to WHO, which then passes them on to the world. But WHO is also closely involved in helping determine the numbers. The data come from several sources, says WHO epidemiologist Christopher Dye; the three main ones are clinics and treatment centers, laboratories doing Ebola tests, and burial teams.

Getting the numbers right is hard for many reasons. Many patients don’t seek medical care, for instance, because they don’t trust the medical system or because they live too far away. Of those who do, some die along the way, and some are turned away because treatment centers are overloaded. Of Ebola people who die at home, some are buried without ever coming to officials’ attention. It can also take time for recorded information to be passed on and entered into data reporting systems.

Testing is a big problem as well. The reports break down the numbers into suspected cases, based mostly on symptoms; probable cases, in which someone had symptoms and a link to a known Ebola case; and confirmed cases, in which a patient sample tested positive in the lab. In an ideal world, all suspected and probable cases would eventually be tested, but testing capacity is lacking. In WHO’s 15 October report, only 56% of the cases in the three countries was confirmed; in Liberia, where testing is huge problem, it was just 22%. (Friday’s report did not break down Liberia’s cases and said the data were “temporarily unavailable.”)

Dye says WHO and other groups are trying hard to improve the reporting on the ground. Among other things, they are trying to set up a system that would provide every patient with a unique identification number. Now, Dye says, patients who enter an Ebola clinic and then have a sample tested in the lab may enter the reports twice, because there is no way to know that the lab and the clinic were recording the same patient.

Are there ways to estimate the extent of the underreporting?

There are. For instance, In a technique called capture-recapture, epidemiologists visit one area or district and determine what percentage of the Ebola cases and deaths there has found its way into official records. “You throw out the net twice, and you compare,” says Martin Meltzer of the Centers for Disease Control and Prevention (CDC) in Atlanta, who is modeling the Ebola epidemic. (The term capture-recapture was borrowed from researchers who study the size of wildlife populations using two rounds of trapping.) But this method is logistically challenging and possibly dangerous, given the hostilities that some Ebola response teams have met, Meltzer says: “I’m not going to ask people to risk their lives to collect some data.”

For a paper published last month, Meltzer and his colleagues used a different technique. CDC has a computer model that, among other things, calculates how many hospital beds should be in use at any given time based on the cumulative number of cases at that moment. For 28 August, the time the paper was written, that number was 143 beds for Liberia; but people in the field told Meltzer that the actual number of beds in use was 320, a factor of 2.24 higher. (These numbers can be found in an annex to the paper.) “We had heard some other numbers that were higher, so we rounded that up to a correction factor of 2.5,” Meltzer says. But it’s a very rough approximation. Also, underreporting is likely to vary greatly from one place to another and over time, he says.

The CDC team’s widely reported worst case projection of 1.4 million cases by 20 Januarywas based on the correction factor of 2.5, and assuming control efforts didn’t improve. It included only Liberia and Sierra Leone; in Guinea, the reported numbers of cases have fluctuated too much to make a reasonable projection, Meltzer says, which could also could be partly due to underreporting.

What does WHO think is a reasonable correction factor?

WHO hasn’t published an estimate. “It’s a point that has been greatly discussed but there is a tremendous amount of uncertainty,” Dye says. For its internal planning purposes, however, WHO uses a correction factor of 2.0. When WHO’s Bruce Aylward said at a press conference last week that the agency is expecting to see between 5000 and 10,000 cases per week by early December, “the difference between the 5000 and the 10,000 is that factor of two,” Dye says. A correction factor of 2.0 would mean that the total number of cases has now crossed 18,000 and the number of deaths 9000.

If the numbers are that far off, should they be published at all?

Even if many cases are missed, the trends in the numbers are still very meaningful. They clearly show that the number of cases has roughly doubled every 3 to 4 weeks and that this trend is continuing. If underreporting  gets worse, however, it may be even more difficult to discern such trends.

Is there any good news in the recent numbers?

There is. The number of new cases in some areas at the epicenter of the outbreak—Kenema and Kailahun districts in Sierra Leone and Liberia’s Lofa County—has been dropping, and that’s not a result of underreporting, Dye says. “It has happened for a sufficiently large number of weeks now that we are confident that it’s a real reduction in incidence on the ground, probably related to control measures,” he says. “Our colleagues working on the ground believe it is, too.”

One important factor has been the increase in safe burials, Dye says. (The bodies of Ebola victims are very infectious.) People in the affected areas have resisted abandoning traditional burial practices that carry a high risk of infection, but in these three areas, local leaders, supported by WHO and others, have come to advocate a change. If that happens elsewhere, Dye says, “we expect to be able to cut out a substantial amount of infection in the community.”

*The Ebola Files: Given the current Ebola outbreak, unprecedented in terms of number of people killed and rapid geographic spread, Science and Science Translational Medicinehave made a collection of research and news articles on the viral disease freely available to researchers and the general public.

Leaked documents reveal behind-the-scenes Ebola vaccine issues

My commentary (synopsis):

Time and Money: GSK could have 24,000 doses ready by January 2015, but they don’t want to invest too much money ramping up production of a drug that isn’t 100% sure to work, be re-sellable, and provide their return on investment. Also – none of the global agencies have offered financing to cover R&D costs and early production if the vaccine fails.

Scaling Up Safely: GSK could make hundreds of thousands of doses if the health safety guidelines were relaxed, and they could use their mega-virus growing vats under bio-safety level 2 conditions instead of bio-safety level 4. That would increase the risk that their facility could be a source of ebola, as workers could get contaminated. So when the public asks why drug companies can’t make millions of doses right away, this is the reality.

From other sources: Current ebola-antibodies coctail from a competitor ZMapp faces similar production limits. There are only about a dozen doses available at the moment, which is why they haven’t sent any to West Africa.

From SCIENCE INSIDER

 By 23 October 2014 2:30 pm

The Ebola virus

Extensive background documents from a meeting that took place today at the World Health Organization (WHO) have provided new details about exactly what it will take to test, produce, and bankroll Ebola vaccines, which could be a potential game changer in the epidemic.

ScienceInsider obtained materials that vaccinemakers, governments, and WHO provided to the 100 or so participants at a meeting on “access and financing” of Ebola vaccines. The documents put hard numbers on what until now have been somewhat fuzzy academic discussions. And they make clear to the attendees—who include representatives from governments, industry, philanthropies, and nongovernmental organizations—that although testing and production are moving forward at record speed, knotty issues remain.

At the meeting, GlaxoSmithKline (GSK) of Rixensart, Belgium, which has the vaccine furthest in development, spelled out how it might scale up production in parallel with the safety and efficacy trials now under way so that the product could be ready for wider distribution by April if warranted. The company expects to have preliminary data in November from phase I studies that analyze safety and immune response in small numbers of people not at risk of contracting Ebola. If those data are positive, efficacy trials could start as early as January in Guinea, Sierra Leone, and Liberia, the three West African countries hard hit by the epidemic.

Earlier discussions suggested that efficacy trials should recruit health care workers and first-line responders like those who do burials or track contacts of known infected people. WHO estimates that there are about 12,000 health care workers in the three affected countries and another 17,500 “community” responders.

GSK is considering two efficacy trials. The largest would take place in Liberia and involve 12,000 people. This study, which could begin in mid-January, would randomize half of the participants to receive the vaccine and the other half a placebo. The study could also have a third arm, GSK said: A vaccine made by NewLink Genetics of Ames, Iowa, that has just entered phase I studies in the United States. The U.S. National Institutes of Health indicated that it was interested in leading this study.

A second trial would start simultaneously in Sierra Leone, Ripley Ballou, who is heading the GSK Ebola vaccine project, told ScienceInsider. “One of the trials may fail for logistics reasons,” he explained. “We only have one shot to get this right.” The trial in Sierra Leone would not use a placebo but instead would offer groups of health care workers the vaccine at different points in time. This “stepped-wedge” trial could involve up to 8000 people, and the U.S. Centers for Disease Control and Prevention has had preliminary discussions with affected countries about staging these studies. Although Guinea is also hard hit, it has the least infrastructure in place to do a trial, Ballou says. “It would be the most challenging place to do a phase III study.”

GSK estimates (see table below, and here) that it will have 24,000 doses of its vaccine ready by January for the efficacy trials. If it cranks up production to full capacity before the those trials are complete, the company could have 230,000 doses available in April, and then could steadily increase capacity to produce more than 1 million doses a month by December 2015.

GSK has made modest investments in scaling up production of its vaccine, and this table projects what it might be able to produce over the next year if it went all out and added several new production lines. The “at risk” noted by the asterisks refers to the company doing quality control without needing to wait for regulatory agencies to repeat the tests.

In one of the background documents, GSK noted that a “critical issue” is what’s known as fill capacity. GSK said there is a shortage of facilities that can fill vaccine vials under sterile conditions in a facility that meets what are known as biosafety level 2 conditions. It suggested the regulatory agencies relax their biosafety requirements. If GSK alone must do the filling, this will affect the company’s ability to produce other vaccines already on the market, including ones that protect against rotavirus, measles, mumps, and rubella, the document said.

The GSK document also outlines a number of proposals to make the first batches of vaccine quickly available, like running some of the quality control tests in parallel and changing the test used to prove sterility of the vaccine from one that takes 14 days to an assay that takes half the time.

Additional studies of the NewLink vaccine will start soon in Geneva, Switzerland, and Hamburg, Germany. A first lot of the vaccine arrived in Geneva on Wednesday, Marie-Paule Kieny, an assistant director-general at WHO, told ScienceInsider. The Canadian government has donated 800 vials of the vaccine to WHO, but is sending them in three separate shipments, Kieny explained. “It just felt too risky to put all eggs in one basket,” said Kieny, who has volunteered as a subject for testing the vaccine herself.

Janssen, a division of Johnson & Johnson, described its plans to speed development of yet another Ebola vaccine strategy that has yet to enter human studies. A delegation from Russia planned to discuss Ebola vaccines being made there, too.

A highly detailed, 28-page document by the Norwegian Institute of Public Health offered “crude cost estimates” for scaling up mass production of Ebola vaccines. By these calculations, 27 million doses of vaccine would cost up to $73 million, and the cost of the vaccination campaigns themselves will add another $78 million to the bill.

Several analyses laid out the complex regulatory and liability issues. The U.K. government argued that “there is a need to provide some form of relief of liability for the producers and distributors of the vaccines” and that WHO should coordinate discussions with regulators. The U.K. government also noted that “affected African countries will have the primary role of authorising or allowing use of investigational vaccines” and said “buy in” from those communities about the clinical trials must be obtained as soon as possible.

As far as financing, the U.K. government contends that a “multi-donor club” should pay for the vaccine development in “the medium term.” But for now, the United Kingdom says it will “unilaterally” cover the costs for purchasing vaccines in Sierra Leone, and it asks the governments of the United States and France to make the same commitment for Liberia and Guinea, respectively.

In a planning document, WHO pointed out multiple logistical issues, including “the ability to safely and securely transport the intervention to the delivery site, the existence of safe and secure storage facilities with appropriate cold chain capacity, the availability of sterile equipment to administer injections.” But to Ballou the greatest question hanging over the vaccine trials is the stability of the countries. “The thing that is going to have the biggest impact is what is happening to the trajectory of the epidemic curve,” he says. “If you progress the current trends 2 months into the future are we still in an environment where you can even consider doing a trial?”

*The Ebola Files: Given the current Ebola outbreak, unprecedented in terms of number of people killed and rapid geographic spread, Science and Science Translational Medicinehave made a collection of research and news articles on the viral disease freely available to researchers and the general public.