The second article in a series examining the pillars of the Gates Foundation’s malaria eradication strategy: Complete Detection, Complete Cure and Complete Prevention covered here.
Today’s rapid diagnostic tests (RDTs) are cheap, fast and easy to use: apply a pinprick of blood. Wait 15 minutes and read the result off visually, like a pregnancy test. RDTs distinguish malaria from other fevers and illnesses, leading to more appropriate treatment, improving both individual and public health. However, RDTs don’t detect malaria in people who aren’t sick but who still might have low level infections. Eradicating, rather than treating malaria, means finding every infection. But today “complete detection” is not practically feasible and might not be possible in theory. Because of these difficulties, detection might be set aside in favor of serial mass drug administration campaigns.
Next generation RDTs will hopefully be ten times more sensitive than current technology. Researchers also want the new RDTs to test for a second biological marker that signals the presence of malaria. Current RDTs check for a malaria protein called HRP2, but it is not expressed by all strains of the parasite. Screening and treating based only on HRP2 would select malaria parasites that are “resistant” to the diagnostic. But so far there is no consensus candidate for a second marker. Also, while the goal is a factor of 10 improvement, current plans call only for testing and confirming a 5-fold improvement.
A much larger problem, however, is that RDTs actually need to be 1,000 times more sensitive than they are today. Otherwise, the best alternative is to skip screening and instead treat everyone in mass drug administration (MDA) campaigns. A paper from Gates Foundation-funded researchers at Intellectual Ventures recently found that “Only diagnostics capable of detecting parasites below 0.1 parasites/microliter result in prevalence reduction on par with an MDA campaign.” Short by a factor of 1,000, current RDTs “are nowhere near sensitive enough and new technologies are necessary if MSATs [Mass Screening and Treatments] are to become the campaign of choice in the future.” Complete detection has a long way to go.
Paucity of alternatives
Such needle-in-the-haystack sensitivity can be had from a laboratory-based, molecular technique called PCR (polymerase chain reaction). PCR can even find a single parasite in a blood sample, a sensitivity of about 0.1 parasites per microliter of blood. But it currently requires laboratory conditions, expensive equipment, and trained technicians. RDTs cost around 50 cents. PCR equipment can cost $5,000 with individual tests running from $1.50 to $20 depending on the technology. Molecular diagnosis, in other words, is very expensive.
Also, a much larger volume of blood is needed, requiring a blood draw (and more highly trained staff) instead of a simple needle stick. PCR takes more time, about an hour or more. People might wander off before test results are in, especially in mass screenings when many or even most people won’t be ill. If blood samples are transported from the field to a centralized testing facility, they will need to be kept at 39 degrees Fahrenheit, according to current CDC guidelines, no mean feat in the high-temperature malaria belt. Considerable efforts are being made to make PCR more field-friendly but PCR cannot substitute for RDTs.
Few new technologies present themselves as alternatives. The Financial Times, in its annual World Malaria Day special section, dedicated an article to advanced diagnostic technology such as a tricorder-like device announced by Nanobiosym. The technology, according to the company, “allows you to diagnose any disease with a genetic fingerprint,” a compact, nanotech alternative to PCR. Company founder Anita Goel said Nanobiosym had not yet developed an “app” specific to malaria because market demand was uncertain. Goel said she had not spoken to the Gates Foundation. Asked to document a proof of concept for the technology, a Nanobiosym spokesperson said that information is “for the moment, highly confidential and proprietary and the company is only able to share under NDA.” Grand Challenges Canada supported a Nanobiosym trial to test for HIV in Rwanda but “there’s really no news to report,” said a Grand Challenges spokesperson. “There aren’t any results being published so far. They are still working on that.”
Two other groups mentioned by the Financial Times are working on a proven approach: magnetic detection of iron crystals called hemozoin. But while extremely clever, the method misses a large number of infections unless the blood sample is drawn at the right time. The approach was ruled out by Gates-funded researchers a year ago. Scientists from the University of Washington and Intellectual Ventures diplomatically concluded that they were “pessimistic about the diagnostic value of hemozoin-based methods at this time as a tool for malaria case management.”
Hemozoin detection (Photo: Intellectual Ventures)
In email, co-author Michael Hegg explained: “Many people have been (and continue to be) fooled by the ease with which hemozoin can be detected…” But it can be absent (or missed by current methods) even when malaria is present during the first part of the parasite’s lifecycle in humans. Consequently, testing people with moderate malaria infections for hemozoin will “miss more than 1 out of 10,” according to Hegg. The problem “only gets worse the fewer parasites there are to detect.” And eradication, as it proceeds, will result in fewer large infections and more smaller ones.
Indeed, “the last malaria reservoirs may the hardest to detect,” according to the motto of the DIAMETER project (Diagnostics for malaria elimination toward eradication). DIAMETER is tasked with finding next generation screening technology. It is managed by PATH and funded by the Gates Foundation. DIAMETER is a bit constricted, “not a very rich pipeline compared to vaccines,” according to Paul LaBarre who heads the project. (And the malaria vaccine portfolio is far from robust.)
“There’s really no silver bullet,” for diagnostics, LaBarre said at a malaria forum in December. “[T]here are many use scenarios and probably no one tool is going to fit all the needs in the way that RDTs have been really instrumental in a one-size-fits-all for control recently.” The costs of RDTs have been driven down because they are one size fits all. If, for eradication purposes, multiple diagnostic technologies move forward, those likely won’t benefit from the same cost-reducing scale of demand. LaBarre, however, does plan “some market shaping to make sure that we can try to achieve the same economies of scale.”
Diagnostics limbo: how low do you need to go?
Malaria’s life-cycle creates a perhaps insuperable detection problem because of a phenomenon called sequestration. Under some circumstances, all parasites in a person’s body sequester themselves outside the blood stream by binding to the inside of blood vessels, for example. Not only do sequestered parasites evade counter-attack by white blood cells and avoid getting filtered out by the spleen, they can potentially confound tests based on a blood sample drawn at just the wrong time. According to Michael Hegg: “Sequestration is an issue for ALL detection methods” that test for the parasite in blood. Sequestration becomes more likely at low levels of infection. Even PCR can, because of fluctuating numbers of parasites, miss infections if they fall below the technology’s limit of detection (LOD).
No one really knows how many parasites must be in a person for them to be capable of transmitting malaria nor how low PCR or some other diagnostic needs to go. According to a PATH document: “existing data are limited, and there is no universal agreement on an exact threshold LOD [Limit of Detection].” At the Gates Foundation, “We spend a lot of time here discussing ‘what does it mean to be infectious?’ ” according Janice Culpepper, who works on malaria at the foundation. “Clearly if you have tons of parasites, you’re likely to be infectious.” However, for very, very low infection levels, assays might find minimal evidence of malaria but, “if you put a mosquito on some of these people, you will infect that mosquito,” said Culpepper in an interview earlier this year. “[W]hile you may not see much in the peripheral blood, they may actually sequester into the skin, into the capillary beds and things. So while you say, ‘wow, this person looks negative,’ they’re actually in places were mosquitos would bite you. They’re waiting.”
Consequently, everyone is a suspect. The foundation convened a meeting molecular epidemiologists, said Culpepper, “to talk about how low do we think we need to go in our testing to understand where the infectious reservoir is.” Conclusion: “we’re going to say you’re infectious if we have any evidence of any parasite anywhere. Because we don’t know. We may change that definition over time as we get some data.” Added PATH’s Paul LaBarre more recently, “Ongoing and planned studies are aimed at providing the evidence to drive more alignment on LOD [limit of detection] requirements.”
There is no sufficiently sensitive RDT on the horizon, and it is infeasible to test all potentially infected people using PCR. Even PCR could miss infections. It appears practically and perhaps even theoretically impossible to realize the foundation’s vision of complete detection.
Slippery slope to mass drug administration
The lack of sufficiently sensitive point-of-care diagnostics makes mass drug administration the preferred, superior strategy over screening and treatment. “If an insensitive diagnostic is used,” wrote the Gates-funded researchers at Intellectual Ventures, mass screen and treat campaigns “will fail to eliminate a large portion of the parasite reservoir” because infected individuals will be missed. “[M]ass-screen-and-treat campaigns are much less efficacious than mass drug administrations,” the study concluded. Similarly, an earlier investigation, again backed by the Gates Foundation, also found that “modelling shows that MDA has a more pronounced community effect, as all current diagnostic approaches will miss a proportion of infected individuals.” Conceivably, everyone at risk of harboring a malaria infection must be treated.
“Certainly the mathematical models and recent experiences confirm that MDA can produce a faster and more durable transmission impact than the test and treat strategies,” said Patrick Kachur, chief of the malaria branch at the Centers for Disease Control.” However, Kachur added that mass drug administration “won’t be practical or appealing everywhere.” Other tools will be needed, such as vaccines and ways to control mosquitoes. However, the World Health Assembly recently voted to target a 90% reduction in malaria by 2030, leaving little if any time for the development and deployment of a vaccine. Bednets have had a substantial impact but might have already reached and fallen from their high water mark of effectiveness. Outdoor repellents have been a new research emphasis, but they don’t take the fight to malaria like drugs and vaccines, as would be necessary to achieve eradication.
Approximately half of the world's seven billion people are at risk of malaria, according to WHO, although just 1.2 billion are considered to be at high risk. The Gates Foundation is funding research into more precise estimates of the extent of the population malaria eradication efforts would need to encompass. But the numbers will be large. In Africa alone, the Malaria Atlas Project estimated 722 million people in 43 countries were at risk of malaria from Plasmodium falciparum.
Next: Complete Cure.
[Article modified 10:15 AM 7/10/2015]