Malaria Atlas Project: Data visualization or special effect?

A map from the Malaria Atlas Project, modified and superimposed on a photograph of Maarten Vanden Eynde’s “IKEA Vase

The Malaria Atlas Project (MAP) found that human interventions this century averted fully 663 million cases of the disease. “Malaria in Africa,” according to MAP, “has halved since the turn of the millennium.”

MAP’s interactive application visually depicts human triumph over disease, malaria driven back, year after year. But is the triumph real or a special effect? More broadly, is malariology accurately representing reality or is it giving malaria a makeover?

Both the visual aspects and the science of MAP invite scrutiny and raise questions. What the maps show sometimes diverges from what the data actually say, for example. And MAP's data sometimes contradict the World Malaria Report when they ought to be nearly the same. It is doubtful that MAP accounted for age shifting while it is certain that MAP did not model the impact of an epidemic of insecticide resistance on the effectiveness of insecticide-treated bed nets. Both decisions might lead to an overestimate of human progress against malaria. Indeed, a different set of choices might show malaria is now resurgent rather than falling.

Images and science are being tweaked elsewhere in the malaria world. A paper in the Lancet on insecticide resistance presents a map that may have been improperly manipulated. In a separate study of insecticide resistance, a senior author "muted" the finding that resistance substantially reduced the protective benefit of bed nets. In addition, estimates from malaria researchers of the economic benefits of malaria have jumped implausibly from $0 in 2010 to $4 trillion today. Malariaologists are also going as far as saying that artemisinin-resistant malaria is spreading in Southeast Asia and threatens a leap to Africa when current published evidence does not support this contention. 

A Lancet ombudsman fended off criticism of one publication saying: “the paper conveys information that suffices for the message,” a philosophy that mis-informs too much malaria research.

These dissimulations may be well-intentioned, but they are not science.

Malaria Atlas Project (MAP)

Modelers make choices that shape the model. A few shards from an IKEA coffee mug became an amphora (pictured above) by the hands of artist Maarten Vanden Eynde. Similarly, the actual shape of malaria’s burden is ambiguous. Shards of malaria incidence data are so scarce that the World Health Organization (WHO) said it can't tell if cases are rising or falling in 32 of the 45 countries in the Africa region.

The MAP visualization mostly displays modeled estimates, not data. Importantly, MAP relies not on reports of malaria cases (which tend to be few and dubious) but parasite prevalence surveys. These surveys test for malaria parasites in blood samples taken from people in numerous different locales over time. MAP combines geo-located survey information with many other factors, like satellite weather data, all processed by minutely engineered statistical methods. Along with the visualization, MAP and other malaria researchers (Bhatt et al.) produced a numerical summary, published in Nature last September: “The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015.”

But for countries like Madagascar, the map and the numbers used in the paper disagree. MAP displays malaria cases estimated from parasite prevalence surveys while, behind the scenes, the aggregate statistics for malaria cases in Bhatt et al. are based on country data.

Maps of Madagascar that should show about the same amount of malaria, based on the bar graph (top), but do not

According to the bar graph, average malaria incidence in Madagascar was roughly 69 cases per thousand people in both 2005 and 2014. The map for 2014, however, clearly shows far less malaria than in 2005. Peter Gething, corresponding author for Bhatt et al., confirmed the disparity, saying it is “entirely correct that there is a mis-match between the time series and the map.”

More than mis-matched, the map and data tell contradictory stories. Visually, malaria in Madagascar appears to be getting crushed. But the data—considered by the researchers as more reliable—say malaria has been rising since 2008, approaching the same level seen in 2000. Malaria in Madagascar looks much better than scientists believe it really is.

Gething, who leads the MAP effort, explained that for some countries “it makes far more sense to base estimates of cases on the country-reported data.” He added: “The list of countries for which the second approach was used is listed in the paper if you are interested.” But the list is not in the paper. Gething did not reply to multiple email requests for the list. However, after the editors of Nature intervened, the MAP tool was changed to list the 11 countries handled like Madagascar where the country data “may not correspond to the parasite-rate derived maps.”

The text in red is a post-publication clarification for MAP (Source: Malaria Atlas Project)

Gething said the 11 countries had smaller malaria burdens and better health systems, leading to more reliable reporting. “Many were unambiguous but inevitably some were borderline situations where arguments could be made for either approach.” But the position of the borderline might have decided the conclusions of the paper. Based on WHO-published country data, reported malaria cases appear to be rising in up to 28 African countries. If some or all of those 28 countries had been chosen, Bhatt et al. might have found a malaria resurgence. Gething would not further detail the criteria used to select the 11 countries.

In concussion research, the NFL stands accused of cherry picking data to produce a milder picture of head trauma. As one critic put it, in excluding unflattering data, “You’re not doing science here; you are putting forth some idea that you already have,” like Maarten Vanden Eynde choosing to make an amphora from fragments of a coffee mug.

Of concern, MAP used country reporting for Gambia, Mauritania and Senegal, three countries which WHO categorized as not having assessable country data. Also puzzling, Senegal has a relative abundance of parasite prevalence surveys. (See figure 2 in the Bhatt et al. supplement.) Senegal even contributed to the much more rarefied data used to transform parasite prevalence into malaria case estimates.

There are presumably good reasons to use country data for Senegal, but Gething would not say what they were. Also, it is not clear if MAP used all the available parasite prevalence surveys or, NFL-style, an unspecified subset. Again, Gething would not say. (He answered 2 of 13 emails which I sent over a three-month period.)

More concerning, what Gething described as “official country-reported data” used by MAP differs radically at times from similar data published by WHO in the 2015 World Malaria Report (WMR). Gething said “some adjustments for known under-reporting or missing data” were applied to the country data. But for Rwanda in 2014, MAP and the WMR present very different pictures of what is happening, although both are based on some form of national reporting.

WHO shows malaria surging in Rwanda (top graph, orange line) whereas MAP (bottom graph) shows malaria tailing off in recent years. (Note: The time axis for the MAP chart runs from 2000 to 2015, one more year than the WHO chart.)

A press account corroborates a sizable malaria resurgence in Rwanda: “Malaria cases in Rwanda rose at 68.6% last year [2014] to reach 1,598,076, against 947,689 cases last year; According to figures released by the Rwandan Ministry of Health.”

It’s not just Rwanda. For 2014, of the 11 nations for which MAP used country reporting, MAP figures undershoot WHO confirmed cases in five: Botswana, Namibia, South Africa, Swaziland and Rwanda.

(Swaziland, as a side note, is not mapped but shows as gray for all years, indicating either intermittent malaria transmission or none. Intentional or not, a gray Swaziland slyly promotes the strategy of “shrinking the malaria map.”)

MAP does not use country data for Burundi. MAP’s survey-based algorithms, however, produce estimates that directly contradict WHO-reported country data.

Malaria incidence in Burundi: Rising sharply according to WHO-reported country data (top, orange line) but falling steadily to its lowest point this century according to the Malaria Atlas Project (bottom).

“We are not sure why the estimates exceed the reported number of cases,” said WHO’s Richard Cibulskis who is also a co-author of Bhatt et al. Cibulskis was uncertain “whether this reflects some double counting of cases or the estimates are just off.” Double counting can be excluded, unless it also afflicts previous versions of the WMR which show much the same chart for Burundi. WHO has not corrected the 2015 edition, so the MAP estimates are “just off.” While data and estimates must be expected to differ in a modeling exercise, the degree of divergence in Burundi might raise proportional concern regarding the model’s validity.

Gaussian process models and reconstruction paste

Maarten Vanden Eynde’s amphora mostly took its shape from reconstruction paste, with just a few pieces of the original blue coffee mug. Similarly, the malaria map for Chad is almost all model. Over the 2000-2015 period, MAP had only a single 2004 study of 960 people.

Red arrow points to the single data fragment, during the 2000-2015 period, to map malaria for all of Chad. (Adapted from Bhatt et al. supplement, Figure 2.)

MAP fills in this data void with exquisite math, computing power and data borrowed from elsewhere to find a steady decline of malaria in Chad, from a peak in 2006 to a low in 2015.

But an amphora is not a coffee mug and malaria in Chad is differently shaped in the eyes of other academics. According to Foster et al., “616,722 malaria cases were reported in 2012, an increase of over 200,000 cases since 2006.” The World Malaria Report also sees malaria in Chad very differently. (Graph not shown.)

Richard Cibulskis suggested that greater use of rapid diagnostic technology possibly increased detection of cases, although “this does not necessarily reflect a true increase in malaria incidence, just an increase in diagnostic effort.”

But Cibulskis acknowledged there were true increases: “Some countries such as Uganda have experienced a resurgence in cases.” To distinguish signal from noise, researchers consider malaria hospital admissions, deaths, diagnostic practices and test positivity rates. I asked Cibulskis if, after taking those factors into account, “can an increase in cases be ruled out for any of the [28] countries which are showing increasing confirmed cases?” In other words, can the possibility that malaria is actually on the rise across most of Africa be excluded? Cibulskis did not reply.

Paying it forward: shifting malaria to older age groups

Malaria interventions frequently target very young children who lack immune protection which develops over time—and by becoming infected with malaria. Averting malaria in the very young reduces cases and overall malaria transmission, but it also prevents acquisition of immunity. As children get older, even where malaria transmission has been pushed down, some will become clinically ill with malaria because of reduced immunity. Overall, cases are greatly diminished but some are “shifted” to older age groups.

Bhatt et al. report parasite prevalence estimates for a cohort aged from 2 to 10. But it is unclear if they adjusted their estimates for the age shifting effects of malaria interventions. If not, their estimates might overstate progress against malaria by leaving the effects of age shifting off the books.

Best scientific practice seems to require accounting for age shifting. According to Briët & Penny (2013): “Many malariological studies limit themselves to examining malaria in children under ten or under five years of age...” However, “analyses for the whole population are preferred as the analyses for children under five do not capture the shifts of morbidity and mortality to older age groups...” I asked Melissa Penny, a co-author of Bhatt et al., whether that paper did as she recommended.  Penny deputized Peter Pemberton-Ross to answer my question, but he didn’t. He said the software used “certainly includes the possibility for age-shifting through its immunity submodel.” He also said that inferring incidence data from prevalence data “may implicitly assume some age-shifting.” But Pemberton-Ross would not say, yes or no, if the Bhatt et al. estimate of 663 million cases averted accounted for age shifting. Peter Gething did not reply to my inquiry about age shifting.

Bed Nets

Spatial only Gaussian Markov random field

Bed nets were “by far the largest contributor,” to averting those estimated 663 million cases, blocking 68% or 450 million malaria episodes, according to Bhatt et al. However, although the MAP interactive application shows the distribution of insecticide-treated nets (ITNs) changing in both space and time, the Bhatt et al. paper used a spatial only model for bed nets. The paper’s supplement states that a spatial only model for bed nets “was preferred over the spatio-temporal model.” Researchers made do with “national means estimated previously” for nets, published in the 2013 World Malaria Report.

Conceivably this creates a mismatch between the maps of bed nets shown by the interactive application and the data used to estimate cases averted, perhaps like the mismatch  of map and data for Madagascar. But a spatial only model for nets might mean a mismatch for all countries.

According to Pemberton-Ross, the spatial only model is just “a technical issue… This choice will have affected the results, but not necessarily by making them less accurate.”

The issue might be fundamental rather than technical, but Peter Gething did not reply when I asked if the conclusion that nets averted 450 million cases of malaria since 2000 rested on a comparatively crude, spatial only model. I also asked Gething whether the interactive mapping tool was displaying spatio-temporal bed net data when, behind the scenes in the Bhatt et al. paper, calculations for cases averted were actually based on a static, spatial only model. Gething did not reply.

I raised these issues to Nature. The editors were responsive to the Madagascar map discrepancy, and appear to have occasioned MAP’s listing of the 11 countries treated like Madagascar “in the interests of transparency,” said Rebecca Walton, Nature’s Senior Press Manager. But the other issues were met with pro forma dismissal: “The paper was rigorously peer reviewed as part of our usual editorial procedures.”

Insecticide resistance—and intransigence

Although bed nets are thought to have stopped 450 million cases of malaria, Bhatt et al. urged that maintaining their effectiveness in the face of insecticide resistance “should form a cornerstone” of future control strategies. But this grave threat to bed nets is entirely absent from the model, as if it’s solely a future concern. (Peer reviewers presumably agreed.)

However, the very distribution of hundreds of millions of nets sparked a proportionally vast rise of resistant mosquitoes, “a worsening situation that needs urgent action to maintain malaria control,” as the subtitle of a recent paper put it. Only a single class of insecticide, pyrethroids, is used to treat nets. Unsurprisingly, mosquitos have developed multiple genetic escape mechanisms, very much as they did when faced with DDT, the primary weapon used in earlier, mid-20th century efforts to eradicate malaria.

Mosquito resistance to DDT increased gradually, ultimately rendering it ineffective and leading to the failure of eradication efforts. With pyrethroids, we seem to be watching a brutal remake of the DDT story. But researchers raise more questions than they answer about pyrethroid resistance: "Is it a problem? How do you know?" asked David Smith, a member of MAP and co-author of Bhatt et al.

In addition to doubting if insecticide resistance is a problem, Smith suggested that dispelling such doubts is nearly impossible: “The experimental unit is the population,” he contended, and “we would need to start collecting data from across the continent,” meaning Africa. A second study, also at continent scale, would be needed to measure the “attributable effect of resistance.” Even more remarkably, Smith said he “would expect the effect size of ITNs to go up overall,” if these two massive studies were somehow completed.

Smith is not alone in denial and casuistry. In Strode et al., researchers set out to investigate “the evidence that resistance is attenuating the effect of ITNs.” But instead, the scientists declared “ITNs are more effective than [untreated nets] regardless of resistance,” which is tautological. Until 100% of mosquitoes are 100% resistant to pyrethroids, an insecticide-treated net will always be more effective than an untreated one.

“Agreed with respect to the tautology,” acknowledged first author Clare Strode. “The ability of ITNs to kill insecticide resistant mosquitoes was significantly reduced when faced with resistance mosquitoes,” but, this message was “muted” in the paper according to Strode. “I originally included a much stronger statement of fact that ITNs kill fewer resistant mosquitoes than susceptible counterparts,” she continued, “but the statistician and Cochrane expert recommended a less bold statement.”

The Cochrane expert, Paul Garner, did not dispute Strode’s account or explain why he recommended a less bold statement. (Also at Garner’s suggestion, the Strode et al. review excluded 914 studies without explaining why.) In 2004, Garner was involved in the Cochrane Review of bed nets that provided much of the basis for the massive scale-up that intervention. Muting the conclusions of Strode et al. might serve to protect the conclusions of the earlier review and the subsequent, massive, bed net intervention that seems to have gone awry.

Many malariaologists demand proof that pyrethroid resistance reduces the impact of nets, a stance akin to the tobacco lobby’s denial that cigarettes cause cancer. According to Clare Strode, “I cannot see how increasing resistance would NOT impact ITN efficacy.” It’s undeniable: “There is no biological basis to argue otherwise,” said Strode.

Nick Hamon agrees: “Yes, resistance compromises efficacy. That is no longer in question.” Hamon runs IVCC, a consortium tasked with developing new insecticides.

Nonetheless recent peer-reviewed papers still ignore resistance. A paper in the Lancet estimating how much malaria might be reduced by further expanding interventions “assumed no loss of effect due to drug or insecticide resistance.” In fact, the authors almost doubled the killing effect of nets in their model, adapted from Menach et al. (2007). Senior and corresponding author, Azra Ghani, did not reply to emails asking how to reconcile today’s stronger insecticide resistance with an assumption of greater killing power than nine years ago.

Insecticide resistance has been modeled. Brady et al. found that resistance cuts the effectiveness of nets by half or as much as two thirds, depending on how swiftly resistance develops. (See Figure 3D.)

In 2013, Penny & Briët determined that introducing nets in high transmission areas with insecticide resistance only reduced transmission by 75% instead of 90%. Penny went on to co-author Bhatt et al., but that paper ignored insecticide resistance even though one third of the population of Africa lived in high transmission settings in 2000.

I am not aware of any papers estimating increased malaria cases and/or deaths resulting from insecticide resistance. IVCC’s Nick Hamon made recourse to “two respected, independent malaria scientists” for a crude estimate of the number of deaths that would be averted if there were a new insecticide to replace failing pyrethroids. According to Hamon: “One scientist gave me a range of 141,000 – 228,000 and another 125,000.” Adding even part of 125,000 to WHO’s estimated 395,000 malaria deaths in 2015 would make for a very sizeable increase in mortality.

Hamon cautioned that “these are ‘back of envelope calculations’ and should be treated as such,” adding that “nobody wanted to be quoted, and for good reasons.” He would not say what the good reasons were. Nonetheless, among themselves, malaria experts countenance disturbingly large increases in malaria deaths resulting from insecticide resistance.

Another mostly insider conversation is the effect of resistance on the infectivity of mosquitos. Against hope and expectation, early indications are that the genetics of resistance also increase mosquito susceptibility to infection by malaria parasites. (See Ndiaith et al. and Alout et al.) Conceivably, not only has the scale-up of bed nets sparked a massive wave of resistant mosquitos, those mosquitos are also more likely to become infected with malaria and thus are potentially more likely to transmit the disease.

Averting the appearance of a malaria disaster: Possible image manipulation in Hemingway et al.

Another paper this year in the Lancet, “Averting a malaria disaster,” drew attention to mounting insecticide resistance and the need to develop new chemicals to replace those that are failing.

However, the map (Figure 2B) accompanying the paper might have understated the extent of the resistance problem. According to the caption, Figure 2B was “reproduced” from an online tool called IR Mapper. However, Figure 2B includes a number of green dots, indicating no resistance, that are not found on IR Mapper, in Sudan, for example. Some yellow dots in IR Mapper, showing possible insecticide resistance in Angola, appear as green dots in Figure 2B, indicating no resistance.

Figure 2B (left) from Hemingway et al. shows a green dot in Sudan but IR Mapper (right) does not although Figure 2B was “reproduced” from IR Mapper. Also, dots in Angola show as green in Figure 2B but are yellow in IR Mapper. (Purple triangles added to identify discrepancies)

I found at least seven such discrepancies between Figure 2B and IR Mapper. In addition, Figure 2B does not display any yellow dots. IR Mapper has been displaying red, green and yellow dots since its inception in 2012, according to Duncan Kobia Athinya of Vestergaard Frandsen, which oversees IR Mapper. Said Athinya: “I cannot speak as to why the Lancet figure does not feature possible resistance (yellow) points, but IR Mapper has followed WHO criteria since its launch in 2012.”

Also unexplained is the green dot in Sudan in Figure 2B. Said Vestergaard’s Melinda Hadi: “I still do not have an answer regarding the green susceptible point in Sudan.” Figure 2B was created in October of 2014 but not published until April of 2016. Studies, and thus dots, have been added subsequently. Also, some might have been removed. But regarding the green dot in Sudan, Hadi said:  “I can confirm a publication was not removed from IR Mapper.”

Perhaps explaining these and other discrepancies, according to Hadi: “the maps in the Lancet article were reproduced. The IR Mapper database was provided to the Liverpool School.” Of possible relevance, IR Mapper includes a “View own data” facility that allows users to create a map from a database.

Hadi explained that yellow dots were left out: “Data points that were classified as possible resistance (90-97% mortality) were not presented in Figure 2.” In addition, Figure 2B “only included data from peer-reviewed publications, so you will note other data points available on the platform (e.g., PMI data) were excluded.” PMI, the President’s Malaria Initiative, collected data in 18 countries.

Asked about issues regarding Figure 2B, first author Janet Hemingway said: “the figure is a screen shot downloaded back in 2014…” Hemingway is Director of the Liverpool School of Tropical Medicine. The discrepancies resulted from the passing of time, according to Hemingway: “Lancet have sat on the paper for almost a year since submission and acceptance so I guess it is possible over this period that IR mapper has been updated for historical data, but we made no alterations to the download.”

Hemingway declined to answer any more questions:  “I have no intention of responding further on this, as there is no further explanation…”

However, the passing of time did not explain the discrepancies such as the missing yellow dots and the presence of a green dot in Sudan and half a dozen other anomalies that surfaced in a non-exhaustive analysis.

I raised these issues with Figure 2B to the attention of Lancet editor-in-chief, Richard Horton. Horton did not reply.

Prompted by the intervention of the Committee on Publication Ethics (COPE), Lancet editor Zoë Mullan relayed an explanation from Hemingway (who had earlier declined to answer questions). Hemingway said: “The single green dot in Sudan he refers to, I suspect is a point that was subsequently corrected if GPS co-ordinates had been incorrectly allocated for example.” Hemingway did not say where the dot could now be found.

Regarding the absence of yellow dots, Mullan explained, perhaps implausibly: “IR Mapper was clearly not showing any yellow dots on the day the authors downloaded the screenshot that became their figure.” Besides the unfortunate timing, Mullan’s explanation would also seem to require that the authors, who are experts on insecticide resistance, didn’t notice the absence of yellow dots that indicate possible resistance, nor did peer reviewers.

In addition to being an editor at the Lancet, Mullan is a trustee of COPE, perhaps creating a conflict of interest in responding to COPE-initiated inquiries. (Mullan’s role at COPE was not disclosed to me; I happened upon it later by chance.)

I also asked Richard Horton directly: “Is Figure 2B a screen capture or reproduced from the IR Mapper database? Why does Figure 2B not show any yellow dots?”

However, Horton only replied that the editors “feel confident that the data reported” in the paper “are accurate and reliable.” He vouched, to some degree, for the data but not for the accuracy of Figure 2B. He did not address the absence of yellow dots.

COPE declined to press the Lancet further. Wrote COPE’s Iratxe Puebla: “Given that the issues relate to a specific figure, we do not feel this falls within COPE’s remit to evaluate...” Furthermore, “COPE considers it beyond its remit to comment on… how facts are presented in individual publications.”

Richard Horton recently criticized COPE for not intervening sufficiently in a controversy regarding statins, bemoaning “the lack of a central institution where scientists who wish to question the actions or ethics of other scientists or scientific institutions can go.”

COPE suggested that I contact “the authors' institution so that they can review and consider what follow up may be appropriate.” Via transatlantic mail, I contacted LSTM board secretary R.E. Holland inquiring about a possible institutional investigation. Holland replied, also by letter: “Having reviewed the issue thoroughly, and having spoken to several experts in respect of resistance incident imaging, I have concluded there is no case for the authors to answer in respect of your complaint.”

Holland’s review assumed that Figure 2B was a screen shot. His letter said: “it is impossible to compare a snapshot of image data from one period to that of another and therefor there is no case to answer.” Holland’s answer was essentially the same as LSTM’s Director, Janet Hemingway. Holland did not explain the absence of yellow dots or the green dot in Sudan. He touted LSTM’s “rigorous research misconduct policy” which had been used in this case.

“[T]he paper conveys information that suffices for the message” 

Figure 2B and the statements by the authors and editors of the Lancet also passed muster with Lancet ombudsman, Malcolm Molyneux. However, Molyneux acknowledged the possibility that Figure 2B was not a screen capture. 

The word ‘reproduced,’ according to Molyneux, “can mean either of the possibilities - a screen-shot or a figure re-drawn from data.” He added: “I really do not think it matters.” In his view, if the authors changed the figure to suit their purposes—including adding dots—they were within their rights: “the paper conveys information that suffices for the message - removing or adding yellow dots or (a few) other dots would make no difference at all to that message.”

Molyneux's statement, “the paper conveys information that suffices for the message,” nicely captures the philosophy that is mis-informing too many papers in malaria.

Placing a green dot in Sudan or anywhere appears to be legitimate in the eyes of the Lancet ombudsman, as long as the number of dots added does not exceed "a few.” Leaving dots out is no infraction, according to Molyneux because “the legend to Fig 2 says ‘reproduced from...’ - it does not say ‘with no subtractions’.” 

He distinguished “falsification of data” from “simplification for purposes of clarity.” However, adding green dots that do not actually represent studies of insecticide resistance means those dots are fake, while changing the color of dots misrepresents the findings of actual studies. It is hard to see how that would not be falsification of data.

Continued Molyneux, “if the authors had been trying to manipulate the figure in order to make their case more compelling, we would expect them to err towards the red in the later time-period (2b)… In every single case you mention of a difference between the IRMapper and Fig 2b, the difference is from red to green, not the other way round.” 

Image manipulation requires no explanation. However, as I wrote to Molyneux, “the title of the paper is ‘Averting a malaria disaster.’ Unless the map shows that there is a disaster to avert then the title doesn't fit… A sea of red and yellow dots might lead readers to conclude that mosquitoes had already won.”

As it stands, figures “reproduced” in the Lancet may differ in unspecified, undisclosed ways from the source in order to convey the authors' message, which might differ from their scientific findings.

Tale of two resistances

If the malaria research community is downplaying insecticide resistance, it is exaggerating the threat of drug resistance in Southeast Asia spreading to Africa. Resistance to artemisinin is not spreading even in Southeast Asia and faces scientifically demonstrated obstacles to overtaking Africa. It’s not happening, but researchers are saying it is.

Arjen Dondorp heads malaria research at the Mahidol-Oxford Tropical Medicine Research Unit in Bangkok. He laid out an accurate chronology of the discovery of resistance to artemisinin-based malaria treatments. Resistance was first found in Western Cambodia, then at the Thai-Myanmar border, in Myanmar, Northern Cambodia, Northeastern Thailand, Eastern Cambodia, Southwestern Vietnam, and Southern Laos.

“Out of the ‘epicentre’ of Western Cambodia,” said Dondorp, “over time the resistant parasite has spread westward, northward, and eastward.” He concluded: “This is spread.”

However, Dondorp’s statement, if not simply false, is not scientifically supported. He described the spread of surveillance, a trick that could equally demonstrate that broken arms or bad breath are “spreading” in Southeast Asia just by conducting surveys in the same places and order he described for artemisinin resistance.

Genetic sequencing has, against expectation, found that nearly every artemisinin resistance hot spot emerged independently, not as a result of spread. Future research might change the current understanding of the epidemiology of artemisinin resistance, but the most comprehensive survey found only three instances of spread out of 112 samples from across the region.

More word play and dissembling are on view in a Lancet paper on resistance in Myanmar that included the word “spread” in its title but adduced little evidence and no claims for it. I wrote two of the authors, saying “the title of your paper, ‘Spread of artemisinin-resistant Plasmodium falciparum in Myanmar’ seems belied by the evidence actually in the paper (and other papers).” I asked them if they would correct “any misperceptions on my part,” but neither Mallika Imwong nor Charles Woodrow replied.

François Nosten, who runs a clinic in Mae Sot near the Thai-Myanmar border, also claims resistance is spreading. “Resistance to artemisinin,” according to Nosten, “has emerged in different places in SEA [Southeast Asia] but then it has spread.” I asked: “Can you describe unpublished data or point to papers where spread is documented?” Nosten, regarded by many as a public health hero, replied not with science but anecdote and sophistry: “We find that over 80% of our patients with malaria have parasites that are resistant to artemisinin. It did not emerge in each and every one independently, did it?” Nosten is correct it did not emerge in each patient independently but that is not at all the same as spread. To establish spread requires DNA sequencing from at least two places; Nosten claims spread based on a single cohort and no sequencing data.

A malaria press tour to Southeast Asia, funded by Malaria No More, featured journalist visits and interviews with Nosten and Dondorp. Stories in Slate and other outlets told readers artemisinin resistance was spreading and threatened a malaria apocalypse in Africa.

Distorted science is creating distorted journalism. An AFP story suggested that the reason artemisinin resistance hadn’t spread to Africa was that “international efforts to contain the spread of resistant parasites have been effective.” It is more the case that biologically it is difficult or impossible to install the multiple genetic changes required to create artemisinin resistance. However, the international containment efforts, by increasing drug pressure, might be forcing malaria down evolutionary pathways which could result in a more compact genetic form of resistance that could be more easily exported to Africa.

Meanwhile, the actual spread of insecticide resistance in Africa is ignored. Another journalist field trip funded by Malaria No More featured Tanzania as the destination. Insecticide resistance might have been among the briefing topics, but it did not appear once in an article for Vice written by one of the journalists on the trip.

No one has died from drug-resistant malaria. “As far as I know,” said Nosten, “there has been no confirmed fatal case.” Meanwhile, according to Nick Hamon’s sources, some part of 125,000 people (or more) have died from malaria because insecticide resistance has reduced the effectiveness of bed nets.

Debasing the currency: $4 trillion drawn on the account of science

Worth less than the paper it’s printed on (Source: Wikimedia)

In 2010, researchers concluded that malaria eradication was unlikely to break even and advised that “financial savings should not be a primary rationale for elimination.” But a few years later, an overlapping constellation of researchers discovered that eradication would quickly generate $4.1 trillion in economic benefits, in just 15 years.

The paper touting a $4.1 trillion windfall “is an advocacy document rather than an academic analysis,” according to Rima Shretta at the University of California, San Francisco (UCSF). Shretta is part of the UCSF group which led development of the 2010 Lancet series which found no cost savings from eradication. Shretta also served on the Action and Investment for Malaria task force that developed the advocacy document projecting $4.1 trillion in benefits.

To reconcile the academic analysis of the 2010 Lancet paper with the later discovery of trillions of dollars in benefits, Shretta seems to suggest scientists are free from the standards of science if they are engaged in advocacy. And functionally, it appears malaria advocacy has detached from science, although much of the advocacy comes from scientists.

The End: Malaria Goes Hollywood

Images, which can surreptitiously mislead, end up exposing a conscious mis-shaping of malaria research. Authors are making undisclosed and perhaps improper choices regarding the visual elements in their papers. However, within the papers, the same authors are free to make any number of choices that can decisively influence findings and there is little or no possibility of suggesting impropriety. The sources of data, how they are processed, type of model and parameters partly or entirely decide the research results. Authors can “mute” statements about the loss in bed net effectiveness caused by pyrethroid resistance. Editors can entitle a paper “spread of resistance” when there is none mentioned in the paper and the evidence contradicts the spread hypothesis. But when the philosophy of managing reader beliefs extends to choices about visual elements, the curtain is drawn aside and we see not a scientist but the Wizard of Oz.

Why you might think like Bill Gates about global health

Video still of Bill Gates during a Washington Post interview

Perhaps you read some of the same publications as Bill Gates, like the New York Times or Slate. You tune into NPR and watch the PBS NewsHour, part of the sacred ritual of thoughtful Americans becoming informed citizens.

From Slate, we know time is running out to eliminate drug-resistant malaria. The Gates Foundation believes this too. But is the foundation’s logic irresistible or did Slate run an infomercial for the foundation funded by a $40,000 grant? The story (including a trip to Thailand) was paid for by Malaria No More which has received $20 million in Gates Foundation grants.

Media matter. As Bill Gates observed, even Theodore Roosevelt’s reform program “wasn’t really successful until journalists at McClure’s and other publications had rallied public support for change.” Now Gates has rallied public support for malaria eradication in Slate, and President Obama tentatively endorsed it in the State of the Union.

It’s not just Slate or only global health. Carefully restricted Gates Foundation grants to NPR, the PBS NewsHour, the Pulitzer Center on Crisis Reporting and other news organizations shape what gets covered, what doesn’t, when and how.

The Gates-funded PBS NewsHour just began a new series on education called “Making the Grade.” The first episode is difficult to distinguish from an earlier Gates Foundation video on postsecondary education. In the NewsHour version, Gates-funded journalists and academics deliver the messages of the foundation’s postsecondary strategy, but neither the foundation nor its funding role are mentioned. 

Trusted media organization receiving Gates Foundation grants are not following good journalistic practices. And like improper food labeling, undisclosed funding misleads news consumers about what they are actually getting.

Readers got nothing on Ebola from the Gates-funded Pulitzer Center for Crisis Reporting until more than half a year after the crisis broke. Pulitzer Center stories appear in an array of top-shelf outlets like the New York Times, Nature, and the Economist, where the center’s first article on Ebola eventually came out. Although restricted Gates funds paid for 59 of 240 Pulitzer Center stories over a 30-month period, neither readers nor perhaps even the editors publishing them could tell which were actually Gates-funded. 

NPR, with its Gates grant, cut staffing for covering climate change in order to expand and transform its global health coverage into an upbeat, advocacy-oriented approach, the opposite of muckraking. Gates funding of this specific initiative is not disclosed. While NPR gives the impression that the Gates Foundation just writes a check to support all of NPR’s good work, it doesn’t.

NPR’s restricted Gates grant actually requires NPR to contribute unrestricted money towards Gates-initiated projects. Ironically, listener donations might be funding broadcast of the Gates Foundation’s news values on public radio.

Which is perhaps why you think like Bill Gates when it comes to global health.

Slate: not so clean

In late December, CNN ran an op-ed advocating malaria eradication, written by the CEO of the advocacy group Malaria No More. In January, a week later, Slate too proclaimed “The World Can Eliminate Malaria.” The article delivered Malaria No More’s messages but was written by a Slate staff writer—funded by the Gates-backed Malaria No More. Jackpot: advocacy runs as news from a credible source.

Nightline veteran Dan Green orchestrates the Gates Foundation’s media and communications grant portfolio. Speaking in 2011 on the “media metamorphosis,” Green observed that with the demise of old media, many news organizations “don’t have a global health reporter anymore.” Consequently, when journalists cover global health, “they need more guidance.” For advocacy groups, according to Green, this created “an enormous opportunity for you to educate those reporters about what it is they need to be thinking about.”

The Malaria No More grant provided reporters with ample guidance:

During the tour, participants will conduct site visits to clinics and treatment centers, attend briefings with health officials and disease experts, hear from organizations working to eliminate the disease and meet with local journalists covering the issue.

In return:

Participants will be expected to produce stories based on the information gathered and contacts made during the tour.

Slate staff writer, Joshua Keating, while possessed of formidable reporting chops, focuses on international affairs and does not appear to write much about malaria for Slate. When domain expertise is short, journalists are at the mercy of their sources. When a journalist’s sources are curated by an advocacy group, the result is not journalism.

Technically, Keating’s trip wasn’t directly funded by Malaria No More. Indeed, it is unlikely Slate would have accepted money straight from an advocacy group. Instead Malaria No More funded the International Center For Journalists (ICFJ). Passing the money through ICFJ, which called the five-day trip a “fellowship,” seemed to overcome any journalistic scruple. As Slate science editor, Laura Helmuth, wrote me:

Josh Keating’s editors were all fully aware of his trip and how it was funded, and we fully support him and the reporting that came out of his trip and his story in Slate.

I asked Executive Editor Josh Levin about  Slate’s policy on accepting funding from advocacy groups. Levin did not reply.

Drug resistant malaria is undoubtedly important. But for Thailand, is it more important than dengue? Globally, multidrug-resistant tuberculosis might be far more urgent and deadly, with half a million cases a year. CDC Director Thomas Frieden believes “There can be no delay” in combating drug resistant TB. But Frieden’s views appear on the CDC blog, not in Slate. (Slate has covered the media’s neglect of TB.)

Slate’s malaria piece takes for granted that a single-disease approach to public health is best, without considering whether health systems might be more effective. In addition, current scientific evidence suggests drug-resistant malaria has not spread even within Southeast Asia and faces surprising barriers to taking over in Africa.

For malaria’s considerable importance, neither Slate nor perhaps any media outlet has written about why Rollback Malaria, the global consortium responsible for combatting malaria, disbanded itself in 2015.

For its grant to Slate, Malaria No More got a narrowly focused piece getting out its key messages. Indeed there were four other ICFJ fellowships, so Slate participated in an orchestrated news boomlet. ICFJ would not disclose the names of the other publications, so the impact (and degree of funding disclosure) are untrackable.

The over $200,000 spent on these trips could go a long way towards putting a journalist on the global health beat. But who needs global health reporters if it’s possible to generate “news” that faithfully delivers an advocacy message?

Structural changes in the news industry have made this easier. Said the foundation’s Dan Green, back in 2011: “You have now media organizations that are far more open to innovative partnerships.” Why? Because “their resources are stretched.” As revenue streams for traditional media dried up, enter the world’s wealthiest foundation as innovative partner.

Promise to say you’re independent

With much solemnity, the foundation and its media partners proclaim the full editorial independence of Gates grantees. But Green acknowledged a “fear” felt by Gates-supported news organizations:

...that fear that as my grant ends, will I get renewed and will any foundation funder, or any outside philanthropic funder, say, ‘Hmm. I looked at the stories and they weren’t all that positive, and they weren’t filled with success. Maybe we don’t want to fund that anymore.’

Green insisted it would be short-sighted for funders to take such an approach. And yet the Gates Foundation seeks demonstrable results, according to Green: “We as funders try to think in terms of outcomes. What would be the outcomes we’re hoping for by telling these stories, by engaging with the content creator?”

The foundation engages with content creators not to give readers a puzzle to solve thoughtfully but to deliver pre-specified, actionable messages. “We really think a lot about ‘Is it reaching an audience that we think is an important audience we need to reach?’ ” Green opined in 2013.  “And, if it is, does it have the credibility and the trust so when it puts out evidence-based information that people say, ‘I believe that. I’ll follow what that says?’ ”

Wearing his journalist hat, Green said, “Now you come from journalism and we don’t sit around talking about messaging. Messaging makes us cringe. Because then it makes us feel that you’re using all the journalists as tools for your messages.” Green concluded, forthrightly: “You might say, ‘Yeah, we are.’ ”

Green defended using journalists as tools because “it’s a mistake to think that if your subject that you care about is getting talked about, and stories are being told and information is out there, that is incredibly valuable.” Journalists get to cover global health; the price is carrying the foundation’s messages. It’s painting by numbers, but it’s still painting.

The dissolution of traditional media, according to Green, brought fragmentation and proliferation of information outlets, and created a news environment with fewer facts and more opinions. Some digital media consultants, said Green, recommended that “the louder and stronger your opinion is, sometimes the more people gravitate to you…” However, even Theodore Roosevelt’s  bully pulpit did not suffice to create change. Regarding the loud opinion strategy, Green said “I’m not a huge fan of that necessarily.” Far better that the foundation’s opinions appear as news.

Like Slate’s malaria piece.

The Pulitzer Center—presented by the Gates Foundation

The Pulitzer Center for Crisis Reporting frowns on free trips. Pulitzer Center-funded articles appear in elite publications like the New Yorker, Nature, the Economist, the Washington Post, Slate, Foreign Policy, National Geographic etc.

But regarding trips, the Pulitzer Center’s ethics policy says journalists “should not normally accept free travel, with the exception of military embeds and other situations in which travel assistance is essential to the reporting.” To further protect its integrity, the center counsels writers to “avoid activities that might interfere with your ability to function as a journalist.” Otherwise, “you may be precluded from working on certain topics for the Pulitzer Center if you're personally involved.”

Although the center closely polices the integrity of worker bee journalists, different standards apply to donors. Many donors write a check with no strings attached, leaving the Pulitzer Center with full editorial discretion. “In recent years,” said Executive Director, Jon Sawyer, “we have consistently gotten 50 percent or more of our budget from unrestricted donations…”

However, the other 50 percent of donations have strings, although the center’s ethics policy seems to guard against any improper influence. The policy asserts: “Donors will not dictate in any way the editorial products of the Pulitzer Center.” But restricted donors, like the Gates Foundation, restrict their grants because they do not believe the Pulitzer Center would, by itself, create the desired editorial products. Influencing the Pulitzer Center’s editorial products is the only reason restrictions exist.

“Over a four-year period our Gates funding has totaled approximately $2.4 million,” said Sawyer. “These were restricted grants but the terms were broad, with funding for a broad range of global health/development topics and educational outreach and full autonomy as to the selection of specific projects, news-media placements and outreach activities.” But the center’s “full autonomy” is over selecting specific projects. The Gates Foundation draws the big picture and contracts out for the needed words and images.

Recall that the Pulitzer Center will disqualify journalists from writing on subjects in which they are personally involved. To guard against donor bias, the center’s ethics policy asserts: “We do not accept donations that raise the possibility, or the appearance, of a conflict of interest.” However, the center’s Gates funding, at minimum, creates the possibility of a conflict. The Gates Foundation is the largest in the world. Most of its donations go to global health and development, the same subjects funded by its grants to the Pulitzer Center. The foundation, far from being policy-agnostic, funds research into policy and advocates for specific approaches to global public health.

This possible conflict of interest is not disclosed to readers nor perhaps even to editors of the publications running stories from the Pulitzer Center. Slate at least disclosed the funding of its story on malaria. Slate didn’t just name the funding intermediary, the International Center for Journalists, it named (sort of) the funder, Malaria No More. Anyone wanting to dig further could discover the Gates Foundation’s $20 million funding of Malaria No More, which advocates for the foundation’s malaria policy, eradication, set by the foundation in 2007.

The Pulitzer Center, with its Gates funding, produced a substantial amount of global health coverage. Over the 30 months of its most recent Gates grant, “we applied Gates funds to support a total of 59 projects,” said Sawyer. “For purposes of comparison, over that same 30 month period we supported some 240 projects overall.” These stories ran with the disclosure of funding provided by the Pulitzer Center. However, one in four is actually the Pulitzer Center presented by the Gates Foundation.

Which 59 projects were Gates funded? Sawyer would not say. He previously mentioned “On some of those [Gates] projects we also drew on funds from other donors.” He emphasized the point: “Also, as point of clarification, our grants to journalists often mix restricted/unrestricted funds.” Sawyer perhaps was suggesting that mixed funding mitigates conflicts of interest. The idea might be that if funding from interested donors passes through intermediaries who stir in some amount of disinterested money, then journalism is not compromised and disclosure is unnecessary.

From the Gates Foundation perspective, however, adding unrestricted funds to those of its restricted grant leverages the foundation’s investment. (It’s possible the grant stipulated that the Pulitzer Center contribute additional funds.) The restricted Gates grant shifted Pulitzer Center resources to more closely match the news values of the Gates Foundation. Maybe not by much; maybe a lot.

Initially, Sawyer wrote me: “Happy to discuss this further. Complicated numbers and we're eager to have it reported accurately.” But when I asked for a spreadsheet listing Gates-funded projects and the funding mix for each, Sawyer did not reply.

Sawyer defended the center’s work: “I hope you'll take the time to read some of the reporting,” he wrote me. “It's quite good!” Read the stories; don’t ask where they came from. But Sawyer is right about quality: the center’s production values are top-shelf, and the finely wrought stories bring attention to a broad array of important but neglected subjects. Slate’s article on the neglect of TB, for example, was supported by the Pulitzer Center. Nonetheless, reporting loses the name of journalism when it comes from restricted funding.

The Pulitzer Center website quotes Joseph Pulitzer: “We will illuminate dark places and, with a deep sense of responsibility, interpret these troubled times.” But Sawyer shed very little light on funding of stories bearing Pulitzer’s name. “Ebola, malaria and other health projects relied in part on Gates, in part on other funding sources,” he said, perhaps again suggesting that mixed funding ameliorated conflicts of interest not disclosed by the Pulitzer Center.

It is true that finding such conflicts is much harder when 59 restricted projects are mixed with 201 that are not. However, in a far from exhaustive search, I came across a speech in which Bill Gates advocated an intervention called seasonal malaria chemoprevention. Later, there is Pulitzer Center article about it, indeed a multi-article project on the subject. Whatever the merits of seasonal malaria chemoprevention, there is no way to determine if its coverage was funded by an interested party.

The Pulitzer Center tells its reporters: “Let the audience know any information about yourself or your sources that might affect its understanding of your work.” Brick-laying journalists are closely scrutinized but the audience has no idea even of the existence of restricted donors shaping the overall news architecture.

The void: Why no Ebola coverage for half a year?

If Gates Foundation influence on malaria, for example, is worrisome, evidence on Pulitzer Center coverage of Ebola raises far more serious concerns: The Pulitzer Center supported no stories on Ebola for more than half a year.

The outbreak began in March of 2014 but no Pulitzer Center stories appeared on Ebola until mid-December. The center’s full name is the Pulitzer Center for Crisis Reporting, and Ebola is the most important global health crisis since HIV/AIDS. Although funded by the Gates Foundation to cover global health, the Pulitzer Center produced nothing on Ebola for the better part of a year.

I conducted my search for “Ebola” articles using the center’s website. (I asked Jon Sawyer for confirmation of my results. He did not reply.) The first article I found is dated December 13, 2014, “The Fight Against Ebola: Donating the Cure,” appearing in the Economist.

According to Sawyer, the Pulitzer Center received what he described as an “extension” grant of $300,000 from the Gates Foundation. It is possible that the timing of the grant coincides with the onset of Pulitzer Center stories about Ebola.

In difficult to parse grammar, Sawyer said: “Gates extension was continuation of previous grant, support for reporting/outreach on broad range of global health/development issues: choice of projects, journalists and outlets left to us.”

Unsure whether that meant “no,” the extension grant did not fund the center’s Ebola coverage, I asked Sawyer again, several times, if the grant was to cover Ebola. I sought details on timing and who approached whom. Sawyer did not reply.

When I inquired of the Gates Foundation’s Bryan Callahan whether the extension grant was for Ebola, he did not reply. Callahan is the foundation’s Senior Program Officer for Program Advocacy & Communications.

Back in 2011, the foundation’s Dan Green, claimed: “We want people to say ‘We get our money from the Gates Foundation.’ ” Later, writing on the foundation’s blog, Green put transparency first among the guiding principles for media grants. Green also promised “in the coming weeks I’ll post another blog listing all of our current investments in this portfolio.” I asked Green for the listing of the foundation’s current media grants. He did not reply.

I asked Amy Maxmen, who wrote stories on Ebola for the Pulitzer Center, whether she knew if her efforts had been Gates funded. “I don't know where the Pulitzer Center gets their funding,” answered Maxmen, without saying yes or no. “I admit I don't ask.”

Maxmen did assert: “I independently came up with the idea for my reporting on Ebola.” However, Maxmen thinks a lot like the Gates Foundation.

The Pulitzer Center’s Ebola project is entitled “Disaster Science During the Ebola Outbreak.”  The center took care to explain this odd-seeming focus: “Research during a disaster can seem frivolous when there aren’t enough resources to handle the immediate response. But in the Ebola outbreak it's become clear that data collection must happen now.” The Pulitzer Center had ignored Ebola for more than half a year and now focused not on an Ebola response but Ebola research—rather like the Gates Foundation.

Had Médecins Sans Frontières (MSF) been the funder of the Pulitzer Center’s Ebola coverage, the stories would likely have come sooner, indeed immediately, and with a different emphasis: the need to act.

In contrast to MSF, the Gates Foundation remained silent on Ebola for months until moments before WHO’s belated declaration of an emergency. Barely beating WHO to the punch, the foundation announced an Austin Powers-sized $1 million dollar grant to “help address the immediate need on the ground.” One day after its token grant, the foundation blogged that meningitis, “could end up being far more destructive than the current Ebola epidemic.” Remarkably, the foundation moved on from Ebola before WHO even declared it to be an emergency.

The crisis worsened. As it reached increasingly apocalyptic scale and the world belatedly mobilized billions of dollars, the foundation chipped in $50 million. The announcement committed $10 million to “emergency operations” but also to “R&D assessments.” For the remaining $40 million, “the foundation will provide further details on its funding commitments to on-the-ground operations and to research and development for Ebola drugs, vaccines, and diagnostics.” The foundation was not going to fund the operational response costing billions but research costing millions. The Pulitzer Center’s Ebola coverage, when it finally came, also focused on research.

The center’s Ebola coverage can be seen as favorable to the Gates Foundation which funded the stories, at least in part. Maxmen’s first article, for example, appearing in the Economist, focused on the silver bullet of blood transfusions potentially curing Ebola. It turned out not to work, and new research contributed little to containing the epidemic. However, one of Maxmen’s stories, appearing in Newsweek, criticized the Ebola response as wastefully managed. Undoubtedly. But the foundation had mostly not contributed to on-the-ground efforts which, in the end, worked. 

In the pages of Nature, Maxmen reminded readers of the importance of malaria and that Ebola was disrupting mass administration of anti-malarial drugs.

Another Maxmen piece provided a reporter's timeline of the world's “plodding attack on Ebola.” It pummeled bureaucratic organizations “bogged down in democratic decision-making processes and bureaucratic policies,” perhaps meaning the World Health Organization. The timeline doesn’t mention the inaction of the Gates Foundation. Nor does the article examine the role of the CDC, which only declared Ebola a top-level emergency one day before WHO.

Latest of all, however, was the Gates-funded Pulitzer Center.

The Economist: “We do not publish articles 'supported' by any organisation”

Maxmen's article in the Economist runs without disclosure of Pulitzer Center funding. I asked Economist science editor, Geoffrey Carr, whether the Pulitzer Center disclosed to the Economist any funding of its work by the Gates Foundation.

Carr replied: “We do not publish articles 'supported' by any organisation, and we certainly do not publish anything funded by anyone.” The Economist is journalism at its purest, or at least proudest.

I pointed out that the Ebola story appearing on the Pulitzer Center site was identical to the one appearing in the Economist. (The Pulitzer Center lists 25 articles and 1 photo as published by the Economist.)

Carr changed tunes: He described Maxmen as “a freelance who seems to have some sort of travel and support grant from the Pulitzer Centre.” Carr added: “I don't see any impropriety in this, since we pay our freelances a market rate for their copy.” 

The Economist  does publish articles supported by other organizations, but without disclosing that support to its readers. (In this regard, the Economist is perhaps the perfect vehicle for maximally credible stories with undisclosed conflicts of interest.) Regarding the question of whether any Gates funding of the Ebola article was disclosed to the Economist, Carr wrote: “I will pass your thoughts on to the Editor of the Middle East and Africa section, whose section this story appeared in.”

NPR: Gates and Soda

Think of your brain as a pie chart, the slices representing the subjects you pay attention to, and the size of the slice indicating how much. If NPR programming influences your pie chart, then your slice on climate change might have shrunk like a receding glacier.

In 2014, NPR cut its environment team to one reporter, according to Inside Climate News, with resources reassigned to “the outlet’s global health and development coverage, which includes a new project launched this summer using a grant from the Bill and Melinda Gates Foundation.”

NPR will not say how much of that project, called Goats and Soda, is Gates-funded. One report said it would “likely not exist” absent Gates funding. But NPR’s Isabel Lara said: “Goats and Soda is possible in large part due to the Gates Foundation grant but it isn't accurate to say that it wouldn't exist otherwise.” Lara is NPR’s Media Relations Director. When asked for details, Lara would only repeat the amount and duration of the grant. “Cannot get more specific than that,” Lara said.

The Gates Foundation’s funding relationship with NPR goes back 15 years. Its most recent grant in 2013 provided $4.5 million to “advance global health and development coverage.”

The Gates initiatives at NPR, however, are not 100%-funded by the foundation. According to Lara: “As is common with many foundation grant agreements, our Gates agreement references NPR’s proposed budget for the initiative which included other resources beyond their investment.” More plainly, the Gates grant requires NPR to help fund the foundation’s projects.

I asked Lara if the “other resources” contributed by NPR included listener donations. She did not reply. However, as at the Pulitzer Center, a restricted Gates grant might be drawing unrestricted funds into the support of the foundation’s news values. Conceivably, listeners are funding NPR’s Gates-designed presentation of global health news.

NPR does not disclose Gates Foundation support for Goats and Soda on its website except, it seems, when Gates or his foundation are the subject. A commentary applauding BIll Gates’ views on solar power, for example, parenthetically disclosed: “As our readers may know, the Gates Foundation is a funder of NPR.” But readers of the laudatory piece on Bill Gates do not know that the Goats and Soda enterprise is mainly and specifically funded by Bill Gates.

Goats and Soda might even be preferentially covering its funder. I asked the author of the commentary, Michael Hayden, if he approached Goats and Soda or vice versa, but he would not say. “Sorry,” Hayden wrote back, “what are you trying to do exactly?”

Unlike NPR’s Goats and Soda, the Guardian puts the Gates Foundation’s logo on all the pages appearing in its Gates-funded development section. Guardian readers do not have to guess what is Gates-funded and what is not. Whether foundation influence extends beyond what it pays for is another question. But a dedicated page describes the funding relationship including the declaration that “content is editorially independent.”

I wrote to Goats and Soda editor, Vikki Valentine, asking whether Gates funding was properly disclosed. Valentine did not reply.

Solutions journalism: turn that frown upside down

Goats and Soda represents not just a switch in coverage from climate to global health. The news production line now turns out a very different editorial product based on a new template, solutions journalism.

In 2012, the Gates Foundation issued a challenge to “find ground-breaking ways to gather and share stories of aid working well.” In the foundation’s view, “The media seems full of stories of corruption, waste and broken systems.”

Responding to the challenge, New York Times writer David Bornstein and colleagues won an initial $100,000 grant from the foundation for an idea called “solutions journalism.” As Bornstein explained:

So much of what we do as journalists is aimed at holding powerful people accountable and identifying failure, which is very important and valuable. But if we stop there, with just identifying failures and the bad actors, it becomes frustrating to people. It’s a broken narrative.

The foundation has supported Bornstein’s efforts with a further $1 million.

Solutions journalism, according to Bornstein, “has more in common with a Harry Potter novel, a quest or struggle, than the traditional journalism narrative.” Harry Potter, of course, is fiction.

Traditional journalists on the global health beat, like Tom Paulson, questioned the solutions emphasis: “A number of journalists, including me, remain concerned that making reporters responsible for emphasizing solutions – along with this Gates push for ‘success stories’ – could undermine basic watch-dogging.”

Paulson leaned toward what he called “cranky” stories. The blog Paulson edits, Humanosphere, ran a story entitled “How Tanzania failed to fix its water access problem.” The piece delivers a very cranky, evidence-based beatdown of the World Bank. The story held powerful people accountable and identified failure. The story was not solutions journalism.

By contrast, a Goats and Soda article on water featured a solution: Bill Gates drinking water “made from poop.” The Gates-funded piece stars Gates and promotes a Gates-funded project. The article’s solutions journalism style, favored and funded by the Gates Foundation, leaves readers with gee whiz wonderment, a sense that there’s an app for the water crisis.

Although the water-from-waste system appears to be the size of small refinery, the story does not delve into what it costs to construct or operate. The price of a gallon of water and whether the system works where there is no sewage system or electricity are not addressed. Broken narratives about the water crisis, however, are avoided.

Change the perception, change the reality

Sally Struthers, circa 1992, told television viewers: “Every year, 10 million third world children don’t live to see their third birthday.” Ten million avoidable child deaths, said Struthers—and that’s on you, viewer. Look: tiny bodies, bloated bellies, skeletal ribs, eyes outlined in flies.

Global Health, 1992 Source: YouTube

Today, moralizing and macabre messages are out. Even the news category “global health” has been left behind. NPR buried its old Twitter handle @nprglobalhealth, pointing followers instead to the new @nprgoatsandsoda. In place of 1990s-era, grim scenes of despair, a Goats and Soda music video shows the modern day “bliss” of living in low-income rural India.

Goats and Soda, 2015

Source: NPR Goats and Soda

Struther’s moral importuning came in television commercials clearly paid for by the Christian Children's Fund. By contrast, what Goats and Soda presents appears as NPR-certified reality, a perception unspoiled by disclosure of Gates Foundation funding.

Very few Struthers-like sermons have appeared in Goats and Soda. Indeed, a story about ethics and the making of blue jeans argued against moralizing. The piece concluded with a quotation from a researcher: “To get people to be more ethical, do not ever present your message as, 'If you're not doing this, you're a bad person...'”

And instead of counting dead children, today we count those who have been saved. Said Melinda Gates at Davos recently, “When we look at the fact that since 2000, childhood deaths have been cut in half, a big percentage of that is because of vaccines.” Quite reasonably, Melinda describes the glass as half full. And the world is doing great on vaccinating children, right?

Omission of bad news is bad journalism—or worse

There is one hiccup: measles vaccination is “falling behind,” according to a story in Goats and Soda. Not to worry, though. Annual measles deaths have fallen from 546,800 to 114,900 since 2000. That’s fantastic—except measles progress actually flattened back in 2007. The good news stopped eight years ago but is still being reported.

More than just measles vaccination is falling behind. Of six targets set in 2010 for global child vaccination, “Just one of these six is on track to be achieved,” according to a report from WHO’s Strategic Advisory Group of Experts (SAGE).  At Davos, Melinda Gates chose to speak about the one target that was on track: introduction of new vaccines.

Goats and Soda’s measles story promised to explain “why the world is falling behind,” but did not. Solutions journalism style, however, it covered “new strategies that seem promising” and “other success stories from the front lines.”

By contrast, SAGE explained what had actually gone wrong:

The targets each relate to different vaccines and diseases, but common threads run throughout: failure to extend vaccination services to people who cannot currently access them at all, and failure to strengthen the healthcare system so that all doses of vaccine are reliably provided.

In addition, the total number of unvaccinated children had “basically not changed” and those at greatest risk became more vulnerable: “Looking closer, the number in the lowest bands is getting worse not better,” SAGE reported. However, few or no journalists explored the halt in progress and backslide in immunizing the world's children. How this failure is possible and who is responsible is not a solutions journalism story. Adding to the broken narrative, SAGE wrote: “The habit of missing major vaccination targets undermines global trust in these efforts…” Global trust, however, remains high because no one reads SAGE reports.

In 2000, Gates Foundation mistrust of vaccination efforts led it to create the Gavi Alliance which now runs the world’s child immunization program. Gavi doesn’t keep track of how many children die for lack of vaccination. (This might be like the Department of Labor not counting the number of unemployed.) Instead, Gavi touts “Another record-breaking year in terms of the number of [vaccine] launches,” the same message emphasized by Melinda Gates. 

These introductions, according to Gavi, “made a major contribution to the unprecedented rate of reduction in under five mortality.” Similarly, Melinda Gates said at Davos: “they are getting the vaccines out now very quickly, and that's how we're saving lives.” Readers might conclude that Gavi and the Gates Foundation have been driving down child mortality more quickly than at any time in history. It's a good story, but it isn't true.

The Gates-funded Center for Global Development reported that new vaccine introductions have made no detectable difference in saving lives, finding only “small and statistically insignificant effects for the three high-priced vaccines promoted by Gavi...”

Vaccine coverage, not introductions, is what saves lives. And according to SAGE, immunization coverage has recently shown “no improvement,” leaving the number of unvaccinated children at 22 million. Children that aren’t vaccinated can and do die from preventable disease in large numbers. “1.5 million children die every year of diseases that could be readily prevented by vaccines that already exist,” SAGE reported, based on a 2008 WHO estimate.

Not a problem for solutions journalism.

PBS NewsHour: copying the Gates Foundation's homework

The Gates and MacArthur foundations both support the PBS NewsHour. Although frequently credited together, this is misleading. The two foundations hold very different, indeed opposing worldviews.

Gates grants are, once more, restricted. A $3.6 million grant to the NewsHour in 2008 supported only global health coverage. A current Gates grant directs $320,000 toward stories that “inform the public” about higher education issues. This media spend hits its mark. 

In January, the NewsHour began a new series called “Making the Grade.” The first episode delivered the same messages on higher education as a Gates Foundation video appearing back in November.

The foundation’s video carried forward messages from an earlier blog entry from Bill Gates, who wrote: “The problem is that not enough people are finishing [college]. More than 36 million Americans—a fifth of the working age population—have gone off to college and left without a degree.” The NewsHour segment described the same problem: “nearly 40 percent of those who go to four-year colleges and some 70 percent of students at community college will never earn their degree.”

Given this problem, the question and title of the NewsHour segment was: “Should more kids skip college for workforce training?”

No one from the Gates Foundation appeared in the NewsHour segment. Their parts were taken by people funded by the Gates Foundation. The NewsHour introduced series host, John Tulenko, as a “special correspondent from Education Week.” Education Week’s parent company has received $12.6 million in Gates Foundation funding. Before joining Education Week, Tulenko worked at Learning Matters, recipient of $1 million in Gates grants.

Tulenko interviewed Anthony Carnevale, head of Georgetown’s Center on Education and the Workforce (CEW) and recipient of $9.7 million in Gates grants. CEW’s postsecondary policy appeared as early as 2012 in a Gates-funded report. CEW’s research informs the Gates Foundation’s current postsecondary strategy. It also appeared in Bill Gate’s blog, in the foundation’s video on postsecondary success, and most recently on the Gates-funded PBS NewsHour.

Tulenko also interviewed Michael Petrilli, president of the Fordham Institute, recipient of $7.8 million in Gates funding. Petrilli, Carnevale and the Gates Foundation argue that too many students go to college and amass debt only to drop out. The solution they propose is that students at risk of dropping out receive advice to consider vocational education instead of going to college.

The only person on the show opposed to re-directing students toward job skills programs was Carol Burris. Burris worried that such career advice would be based on stereotypes, especially racial stereotypes. Of the three academics interviewed, Burris was the only one not funded by the Gates Foundation.

For journalism, however, the question is not whether the Gates Foundation’s postsecondary policy should be followed or not. The issue is that the PBS NewsHour ran a story as news that is not distinguishable from the advocacy of a funder.

The Gates Foundation’s role as funder in the story also was not visible to viewers. The credits for the segment stated that principal support came from the Noyce Foundation. The Noyce Foundation is defunct. And although NewsHour spokesperson Nick Masella said “NewsHour's education funders are listed on our education web page,” the Noyce Foundation is not among them.

I asked Masella why the NewsHour used a “special correspondent” rather than a NewsHour correspondent and whether Education Week contributed funding. Masella did not reply. Similarly, Masella would not say whether its Gates Foundation grant supported the segment, only that: “The PBS NewsHour credits the Gates Foundation every night on our broadcast, as we do with other foundations, in accordance with PBS's funding standards.” 

But the NewsHour gives viewers the impression that the Gates Foundation supports all the NewsHour's good work, when actually Gates money funds stories only on education, stories which do not disclose this restricted funding. By contrast, when the NewsHour covers, for example, rail issues, it clearly states that it receives funding from BNSF. 

More in line with the impression PBS gives to viewers, the MacArthur Foundation does support all the NewsHour's good work. MacArthur's  $1.5 million grant is not restricted. Although MacArthur does issue some restricted journalism grants, according to Kathy Im, MacArthur’s Director of Journalism and Media: “When we have a well-established relationship with a grantee and have confidence in their editorial vision and dissemination strategies, we tend to provide unrestricted support in order to provide maximum flexibility to the organization and its leadership.”

Gates Foundation v. the People of the United States

MacArthur supports journalism in the public interest; the Gates Foundation supports journalism in support of its policy interests. The MacArthur Foundation believes in open society principles; Bill Gates believes institutions of civil society are iffy: “The closer you get to it and see how the sausage is made, the more you go, oh my God!” Gates told the Financial Times. He wondered whether in American democracy, “can complex, technocratically deep things – like running a healthcare system properly in the US in terms of impact and cost – can that get done?”

Imagine, continued Gates, “the idea that all these people are going to vote and have an opinion about subjects that are increasingly complex... Do democracies faced with these current problems do these things well?” Perhaps if they are shown how by their betters.

Whether foundations “do” global health better than democracies and the institutions of civil society is a question that is not asked. Instead of holding the Gates Foundation accountable, a number of influential journalists at trusted news organizations write to foundation storylines and pay down their mortgages with foundation funding.

Muckrakers might have called this corruption. At the Gates Foundation, it’s philanthropy.


Article History
14 February: Section with quotations from Economist science editor Geoffrey Carr added

Academia and advocacy conflict on economics of malaria eradication

[Please see the clarification at the end of this article.]

Don’t ask where the numbers came from, but beating malaria is a great way to make $4 trillion dollars.

In July, the Rollback Malaria initiative rolled out its “exceptional case” for investment in eliminating malaria, a plan promising a 40:1 return on investment (ROI), rising to 60:1 in sub-Saharan Africa.  Malaria elimination will purportedly bring a multi-trillion dollar windfall: $700 billion within a few short years (by 2020), growing to an impressive $4.1 trillion by 2030.

(Source: Rollback Malaria, Action and Investment to defeat Malaria 2016-2030)

However previous research, also conducted by advocates for malaria elimination, found insufficient basis for using financial benefits to justify the costs of fighting malaria.

Rollback Malaria (RBM) would not explain how it arrived at its inviting rates of return, declining to provide a spreadsheet. “The Excel sheet has data from all countries that was modelled up to give the global costs so it isn’t terribly helpful,” said Helen Prytherch of the University of Basel. Prytherch would not send the spreadsheet and suggested talking with the lead economist instead.

The process of peer review prevented bringing forth the details of the estimate. “We are working on your request,” said Prytherch, who continued:

“Several scientists from different institutions worked over a two-year period to establish the new malaria targets, cost them and then to establish and implement a cost benefit analysis. They are now preparing scientific papers to get the work into the public domain. They should be ready for submission by end September.”

However, in 2010, a consortium of pro-elimination researchers concluded that "policy makers should not view the generation of substantial short-term or medium-term cost-savings as a rationale for elimination until more robust evidence is available to suggest otherwise."

Investigators at the University California at San Francisco (UCSF) subsequently sought but did not find robust evidence of cost saving. Findings from ten case studies “do not change the conclusion” that cost should not be viewed as rationale for elimination, according UCSF’s Rima Shretta. Shretta said “malaria elimination should not be pursued merely on the grounds of cost-savings as these often fail to capture all the externalities garnered by disease elimination.”

Of RBM’s plan, Shretta says “it is an advocacy document rather than an academic analysis.” RBM’s macroeconomic analysis “was done using published data rather than an empirical analysis.” In the reinterpretation of existing results, RBM “used a full-income approach which produced larger benefits than some other approaches.” Several previous studies “have not been able to do this using short term projections,” according to Shretta.

Either malaria advocacy is going to depart from established academic research, or the academic consensus might be about to change. “I think if an academic analysis supports elimination – great,” said Shretta. Rather than argue against such an analysis, Shretta seems to have adapted to its inevitability: “the benefits are often underestimated so [elimination] should not ONLY be based on an economic argument but ALSO a social, development and moral perspective.”

On the present trajectory, science will soon give its blessing to malaria eradication being wildly profitable in addition to its other virtues.

Clarification

Posted August 26, 2015

Since publication of this article, Rima Shretta disclosed to me her membership in the task force for Action and Investment to defeat Malaria (AIM). AIM produced the estimate of $4.1 trillion of economic benefits to be gained from malaria elimination examined in my article. Shretta would not explain why she did not inform me of this critical fact. However, it is the responsibility of the journalist to establish the independence of an observer and I regret that I failed in this regard.

Shretta disputes multiple aspects of the article. Prior to disclosing her involvement in AIM, Shretta requested a correction to the article:

I believe my opinion has been mis-represented. I do not dispute the analysis in AIM. I also have not adapted to its inevitability. The statement below is incorrect:

"Rather than argue against such an analysis, Shretta seems to have adapted to its inevitability"

We strongly believe in the case for elimination and its returns - financial and otherwise. In my opinion often the analysis does not make the case strong enough because of the other factors that cannot be measured well.

I responded in part:

I asked Richard Feachem if there was new evidence on the matter of costs and benefits. He referred me to you. You stated there was no new evidence to change the conclusion of the 2010 [Lancet] paper.

So something has to give. There is a $4 trillion discrepancy. 

Shretta, now stating she was on the AIM task force, then requested multiple changes to the article, including re-working or deleting all quotations except one. She wrote in email: “I am fine with the statement that ‘malaria elimination should not be pursued merely on the grounds of cost-savings as these often fail to capture all the externalities garnered by disease elimination.’ “ However, “the rest of the quotes are out of context…”

Shretta did not reply to a question regarding her involvement with AIM. However, I withdraw the statement that Shretta adapted to the inevitability of the AIM document.

Post-publication, regarding the key question of reconciling the Lancet paper with AIM, Shretta wrote: “The Lancet paper warned on rationalizing elimination based on a financial argument alone.” Arguably, this is a considerable misinterpretation. The Lancet paper warned that short- and medium- term economic benefits cannot be part of an argument for elimination, whether alone or in conjunction with any other arguments.

Shretta’s penultimate communication states:

The AIM is based on country level data on malaria disease and a transmission model that forecasts the disease over time. This was then costed out. The analysis on the benefits is from published data. We at UCSF do not dispute the findings of AIM.

One less apocalypse: Questioning the spread of drug-resistant malaria

Drug resistance has twice started in Southeast Asia, both times leading to massive epidemics of untreatable malaria in Africa. Only the introduction of artemisinin combination therapy earlier this century beat back the most recent wave of drug resistance. Now artemisinin is buckling, leading to understandable worry about yet another resistance apocalypse. But current scientific evidence contradicts the narrative of doom voiced by journalists (including me) and much of the malaria research community.

Artemisinin resistance has barely spread but instead popped up on its own, evolving independently in areas scattered across Southeast Asia. The effort to “contain” resistance by wiping out malaria in the region will not prevent independent emergence in Sub-Saharan Africa where home-grown resistance could develop undetected by today’s weak surveillance system.

Artemisinin resistant malaria results from changes to a complicated genetic network that will be difficult to infiltrate into other parasite populations without it coming apart. However, elimination efforts Southeast Asia both strengthen resistance and streamline its genetics for easier transmission abroad, fomenting the very apocalypse it supposedly seeks to avoid.

Not spreading even in Southeast Asia

Drug resistant malaria is scarcely spreading at all in Southeast Asia, even within national borders. The most comprehensive survey found only three instances of spread out of 112 samples from across the region. Parasites thought to have originated in Cambodia were found in people tested near the border with Vietnam. “All other mutations appear to have arisen independently,” scientists concluded. Other researchers concur that resistance “is primarily due to the proliferation of newly emerging mutations…” Rather than spreading, most instances of resistance “appear to be localized to a relatively small geographical area…”

A paper on resistance in Myanmar includes the word “spread” in its title but adduces little evidence and no claims for it. Scientists found “strong evidence” of resistance in Myanmar “including regions close to the Indian border in the northwest,” a worry because past drug resistance is thought to have spread first to India before leaping to Africa. However, resistance is not spreading, according to the authors, rather it “extends” across Myanmar. Seven individual mutations appear “to have arisen independently” more than once, pointing not to spread but de novo emergence.

Resistance has not spread to Myanmar: “Contrary to the widely assumed scenario,” concluded another research group, “we found no evidence of westward spread of artemisinin resistance from Cambodia to Myanmar.” So far in Laos and Bangladesh, mutations associated with resistance are “absent or found at much lower frequency,” additional evidence against regional spread.

Sizable population movements within and between countries seemingly ought to create an equivalent dispersion of resistance. Why that hasn’t happened is “a very good question,” said Philippe Guyant, co-author of a paper on malaria and migrant workers in Cambodia. “I don’t think there is a definitive answer to it given the current state of knowledge.”

But the domino theory of spreading resistance, although widely-discussed and deeply worrisome, is not supported by current scientific evidence which shows that drug-resistant malaria is scarcely spreading even within Southeast Asia.

Genetic complexity militates against spread

Conclusive evidence of artemisinin resistance emerged in 2008, but the complexity of the underlying genetics frustrated efforts to find a molecular marker until 2014 when mutations in a gene called Kelch 13 (K13) were finally implicated.

K13 mutations appear necessary but not sufficient for resistance; supporting mutations appear to be needed. Scientists inserted resistance-associated K13 mutations into parasites susceptible to artemisinin. Modified parasites originally from Cambodia showed a greater increase in resistance than other genetically altered lines, “suggesting a role for additional parasite factors in augmenting K13-mediated resistance…” Four other genes have been connected with resistance in Southeast Asia. In two African samples, scientists found the supporting mutations “were rare or absent… suggesting that they are the product of evolutionary selection within Southeast Asia.” In Southeast Asia, the K13 mutations appeared only after the supporting cast was in place.

Right now, artemisinin resistance in Southeast Asia is tightly bound to an interconnected set of genetic changes particular to its evolutionary history, a history that differs greatly from much of Africa—although not all.

For artemisinin resistance to spread to Africa it will have to overrun incumbent populations. However, the delicate architecture of resistance—multiple mutations riding several different chromosomes—is likely to be pulled apart by the sexual recombination of malaria parasites. Years ago, malaria dragged down the combination drug sulfadoxine-pyrimethamine by incrementally accumulating changes. By contrast, a mutation to K13 seems to need simultaneous changes elsewhere in the genome to balance fitness costs, compete with other parasites or both.

According to Olivo Miotto, co-author of a paper on the genetic architecture of artemisinin-resistance:

“The fact that the main Kelch 13 mutations emerge only on a certain genetic background suggests that there is something special about those parasites. Perhaps it is this ‘something special’ (associated with the genetic background we have identified) that needs to spread in Africa before Kelch 13… I’m pretty sure that Kelch 13 mutations alone will not be enough.”

Another obstacle to the spread of resistance to Africa is far lower drug pressure there. Malaria in Southeast Asia is less intense, so people generally do not acquire immunity and fall ill when infected. The sick seek and receive treatment at very high rates, piling on drug pressure. By contrast, “Right now, only a portion of African parasites get exposure to the drug,” observed Miotto. In much of Sub-Saharan Africa, more intense malaria means greater natural immunity, leading to a greater number of infections that cause no sickness. The unsick seek no treatment. If parasites aren’t exposed to the drug, resistance to artemisinin confers no fitness advantage and will be swept from the genome.

Unknown unknowns

However, much remains unknown and possible parallels with the past are cause for concern. Although artemisinin resistance appears to rely on more than K13 mutations, according to Miotto, chloroquine resistance, early in its development, also might have needed more than one mutation. For chloroquine, “the key marker was identified, but the story may still be incomplete—don’t confuse that with it being simple… We could only study the aftermath,” which pointed to a mutation in one gene. According to Miotto, malaria could yet produce a single K13 mutation that prevails against artemisinin.

Chris Plowe at the University Maryland concurred: “What is happening now with artemisinin resistance may not be all that different from what happened with chloroquine, sulfadoxine and pyrimethamine resistance in the past. We are just witnessing it in real time with a lot more data.”

Continuing research might find more evidence for spread. According to Shannon Takala-Harrison at the University of Maryland, with increasing numbers of samples, “we are seeing additional evidence for spread as well as independent emergence of mutations.” She looked forward to discussing “more concrete results and conclusions as they become available.”

At this particular time, however, there is astonishingly little evidence of spread and sizable genetic and environmental obstacles working against it.

Policy discomfited by evidence

The current policy of elimination fits somewhat awkwardly with current evidence. If artemisinin resistance mostly emerges independently, increased surveillance in Africa rather than containment in Southeast Asia might be more sensible. But according to Patrick Kachur, head of the malaria branch at the Centers for Disease Control (CDC), eliminating all malaria in Southeast Asia makes good sense: “I think the threat of artemisinin-resistance spreading to Africa is a compelling reason why global malaria advocates should be interested in eliminating malaria in Southeast Asia.” Also, countries in the region have their own, additional reasons for wanting to be completely free of malaria, according to Kachur.

Elimination has been “a moderately effective advocacy message,” Kachur said. It is one the malaria research community seems loathe to change even though science does not clearly support it. Neither Kachur nor Plowe responded to emails asking them to contradict the hypothesis that drug-resistant malaria is not actually spreading. Emails to the Gates Foundation also received no answer.

The narrative of doom obscures an all-too rare bright spot in malaria and global health: the pipeline for new antimalarial drugs is incredibly robust. Although grim headlines say, for example, “No 'plan C' drugs available,” multiple new candidate drugs and entire new drug classes have been discovered largely under the umbrella of the Medicines for Malaria Venture, a public-private partnership started by the Gates Foundation.

However, Bill Gates adds his voice to the apocalypse chorus. In a YouTube video, Gates described the possible spread of resistance as “the biggest disaster for control ever.”

Next Gates says: “We’re trying to figure out if we can do local eradications.” But if resistance, rather than eradication, were the primary concern, elimination is no longer automatically the right strategy.

“Drug resistance is driven by drugs,” as Olivo Miotto put it. Elimination maximizes drug resistance, making it stronger and more heritable as drug pressure reshapes and streamlines the initially complex genetics of resistance. This is “the core question” for Miotto. “Drug resistance doesn’t come from heaven; we create it, we encourage it.” He called for better models “to predict the outcome of intervention as we move forward,” saying “responsible approaches to deploying drugs are key.”

Nonetheless, CDC’s Kachur said “enthusiasm is high among global and subregional malaria subject matter experts” for elimination.  Chris Plowe argues that “What the independent emergences tell us is that containment is not likely to work, so by eliminating we can at least try to prevent the most fit, viable and dangerous forms from spreading.” However, elimination propels greater fitness, viability and more dangerous forms that are more likely to spread.  Per the title of a 2009 paper about eliminating artemisinin-resistant malaria in Cambodia, “The last man standing is the most resistant.”

Mathematical models show elimination is unlikely to work. Gates Foundation-funded researchers found that extinguishing malaria was not possible in many places, including in Southeast Asia: “Prospects for elimination in Myanmar and southern Thailand do not appear to be favorable.” Myanmar, recently announced the goal of eliminating malaria.

In another study, “An optimal control strategy to reduce the spread of malaria resistance,” even models using both mass drug administration and insecticide measures fail to completely get rid of drug-resistant malaria. “We think from our models that it is true it is not possible to eliminate drug resistant malaria just using mass drug administration and insecticide,” confirmed co-author Fatmawati Armawi of the Universitas Airlangga.

With elimination exacerbating resistance, evidence-driven policy would seem to suggest reducing drug pressure in Southeast Asia and intensifying surveillance in Africa. The edges of the malaria belt in Africa have low transmission like Southeast Asia. In addition, countries that have advanced toward malaria elimination also have low transmission coupled at times with high drug pressure. According to Miotto, “These should probably be our ‘sentinels’ ” for artemisinin resistance in Africa.

At present, however, malaria science and malaria advocacy appear to have separated.

Malaria elimination efforts jeopardizing early pregnancies in Southeast Asia

Bill & Melinda Gates in Pailin, Cambodia (Photo/video still: Gates Foundation)

Large-scale drug administration campaigns are putting early pregnancies at risk in Southeast Asia where efforts are under way to eliminate malaria. World Health Organization (WHO) treatment guidelines state that frontline antimalarial drugs based on artemisinin should not be given to women in the first trimester of pregnancy. Animal studies have found artemisinin caused early termination of pregnancies and birth defects.

But few programs test for pregnancy, according to the US Centers for Disease Control (CDC). Even a malaria treatment project funded and visited by Bill & Melinda Gates in Pailin, Cambodia seems not to be screening for pregnancy and departing from WHO guidelines.

Eliminating drug resistance & gearing up for global eradication

In Southeast Asia, the countries surrounding the Mekong River are seeking to completely eliminate malaria. The driving force comes from concern that drug-resistant malaria might spread from Asia to Africa, which has happened twice in the past at enormous human cost. Now artemisinin is under threat. In addition, elimination efforts in the Mekong region can provide valuable experience for the much greater ambition of global malaria eradication. As Bill Gates put it, “We’re trying to figure out, can we do local eradications?”

Malaria elimination leans heavily on large-scale administration of the frontline antimalarial drugs, artemisinin combination therapy (ACTs). Some campaigns test for infection, the “screen & treat” approach. Other campaigns simply treat everyone regardless of infection status in mass drug administrations (MDAs).

“It’s not possible to generalize,” how drug campaigns handle pregnancy, according to Patrick Kachur, malaria branch chief at the CDC. There are many campaigns and multiple institutions behind them, sometimes in partnerships. According to Kachur:

"In some of the MDA trials or pilot programs currently pregnant women were excluded by design.  In others they were not (or that detail has not been reported).  In most of the test and treat approaches pregnant women were usually included (occasionally receiving a different treatment regimen than children and non-pregnant adults if they tested positive)."

As a result, women who are or might be in the first trimester of pregnancy are being given artemisinin in some campaigns. Some pregnant women treated for malaria might not even be infected with the disease. WHO guidelines call for quinine and clindamycin in the first trimester of pregnancy--when the mother actually has malaria.

Artemisinin appears to be safe for mothers in all stages of pregnancy. However, in animals, artemisinin is embryotoxic and causes birth defects. (See review here.) The animal exposures to artemisinin were not extreme but adjusted to be near the equivalent, WHO-recommended therapeutic dose for humans. Even so, animal models can be misleading. The shorter development period in rats might be far more sensitive to artemisinin exposure than the more prolonged development process in humans and that “could have a protective effect for human fetuses,” as one researcher noted. Artemisinin might be safe—or not.

Assessing risk: prioritize obstetrics or malaria control?

In 2007, researchers wrote that larger, “methodologically rigorous” studies of artemisinin and pregnancy were “urgently required.” The authors worried that “early pregnancy loss will be difficult to detect, especially in communities where artemisinins are likely to be used most frequently.”

But more recently, concerns have partly subsided, perhaps more among malaria specialists than obstetricians. “My concern has gone down on this issue,” said Brian Greenwood, of the London School for Hygiene and Tropical Medicine and co-author of the 2007 paper calling for examination of artemisinin safety. More recently, Greenwood said: “There is now extensive clinical experience that ACTs are safe in the second and third trimesters but, not surprisingly, less data on exposure in the first trimester.” 

There has been no larger, methodologically rigorous safety study; it might not be possible to perform ethically. Instead, “the numbers of documented cases of exposures in the first trimester is still fairly limited,” said Greenwood, “in the hundreds, so a rare event could not be excluded and it would be difficult, or probably impossible, to detect fetal resorption.” Fetal resorption is defined as “The disintegration and assimilation of the dead fetus in the uterus at any stage after the completion of organogenesis which, in humans, is after the 9th week of gestation.” 

The Gates Foundation, asked whether artemisinin posed a health risk in early pregnancy, demurred. Foundation spokesperson Bryan Callahan instead suggested seeking comment from WHO “on whether they are planning to revise their normative guidance.” Callahan expected that WHO “would take available scientific research into account in reviewing their guidance, including a growing body of observational research on pregnant women.” Meetings in coming months could see the WHO guidelines revised.

However, the safety of artemisinin in early pregnancy is not established by evidence that would lead to regulatory approval in the developed world. Physicians in the United States would not administer artemisinin to a pregnant woman in the first trimester, particularly in the absence of a malaria infection, as is happening in countries like Cambodia and other nations in the Mekong River region.

Wealthy countries don’t have malaria and so can prioritize pregnancy. Still, a public health policy that increases pregnancy risks to mothers living with less money and more disease makes for a problematic ethical situation at best.

'Programs should screen for pregnancy'

“I think programs that use MDA should provide pregnancy testing like we do in Wellcome Trust units,” said Rose McGready from the Shoklo Malaria Research Unit in Mae Sot, Thailand. According to McGready, proving safety in first trimester drugs or vaccines “is extremely difficult and more so in countries where health systems are not working well.”

Even regarding currently approved drugs, McGready asked: “how much data do we have for them? Many are assumed to be safe [like] quinine; but only proper comparative studies will provide a definitive answer.”

Melinda Gates has been campaigning for “Putting women and girls at the center of development,” as she wrote last year in Science. According to Gates, the foundation focused in its earliest days on research. Its second phase included an emphasis on delivery. For the foundation's third incarnation, “what I’m making sure we add on now is the women and girls lens,” she recently said.

But that lens seems to have been absent when Melinda and Bill Gates visited a screen and treat program in Pailin, Cambodia earlier this year.

Blogged Bill Gates:

“we walked to a local school where the screening is taking place. That morning, about 120 people had come to get their blood drawn and tested for the malaria parasite. They also answered a few questions designed to find out whether they might have been exposed to the parasite (e.g., ‘Do you work in the forest?’).” 

Gates did not mention questions about pregnancy or pregnancy tests.

Dance of the blameless

Asked whether the Pailin program included pregnancy screening, foundation spokesperson Bryan Callahan replied: “We recommend that you direct any detailed questions to MORU,” Mahidol Oxford Tropical Medicine Research Unit. MORU was the foundation partner responsible for the project and orchestrated the Gates’ visit to Pailin. According to Callahan, “Like all foundation grantees, MORU was required to secure country-level IRB approval for its malaria treatment protocols, and these protocols include a pregnancy screening component.”

Callahan would not confirm that other Gates grantees were screening for pregnancy, although he acknowledged that he had "received the feedback that I had requested from partners" as part of what he termed "due diligence" in answering the "chemotherapy for pregnant women question."

Callahan would not provide a list of the Gates Foundation partners. “We list all of our Malaria program grantees on our website, and you are free to contact them,” said Callahan. A search for “malaria” on the foundation’s grant website returns 1,000 matches. 

Asked whether MORU specifically was testing for pregnancy rather than just required to, Callahan answered: “The partner is MORU, so you have an answer to your question.” The answer, however, was not “yes.” Pressed further, Callahan said: “As I have stated several times, foundation grantees are required to use protocols approved by local IRBs. You need to consult directly with MORU on your question.”

Asked for the most appropriate contact at MORU, Callahan supplied a link to the MORU contact page.

Buck passed

According to MORU’s Lorenz Von Seidlein, “We are coordinating several studies which include mass drug administrations and are funded by the BMGF,” the Bill & Melinda Gates Foundation. Regarding the scope of the effort, Von Seidlin wrote: “drugs have been administered in Vietnam and… in [the] Thai-Myanmar border areas [while] drug administrations are planned in Pailin/Battambang Cambodia in the coming weeks and in Laos at the beginning of next year.”

To describe the project, Von Seidlin pointed to a paper entitled “Fighting fire with fire.” It likened targeted malaria elimination to the tactic of “back burning” in battling forest fires. According to the paper, “all community members whether infected or not are offered antimalarial treatment.” The three-day treatment is given a minimum of three times, one month apart, creating multiple possible exposures of first trimester pregnancies. (It’s not clear that such a regimen has been tested in animal models. Some animal studies found pregnancy harms from artemisinin increased with dose size.)

The paper does not mention pregnancy screening. Asked in email, “Are the mass drug administrations screening for early pregnancy?” as the Gates Foundations says is required of its partners, Von Seidlen did not reply.

Echo?

The nonprofit FHI360 is administering a malaria grant from the Global Fund, also focused on Pailin. Asked if pregnancy screening was part of the program's protocol, an FHI360 spokesperson "reached out to our experts" but never replied to the question. FHI360 touts its namesake "360° perspective" and lists "gender" as a practice area.

WHO's Walter Kazadi coordinates the Emergency Response to Artemisinin Resistance (ERAR) in the Greater Mekong Subregion. Kazadi did not reply to email asking about anti-malarial administration and pregnancy screening.

Eradication: an experiment

Whether the drug-based strategy will eliminate malaria is not known. According to Von Seidlen’s paper, “It is not clear what coverage is required to interrupt transmission, a question mathematical modelers may be able to answer.” However, Gates-funded modelers have already said mass drug administration alone will not eliminate malaria in Southeast Asia.

Bednets and insecticide spraying will be hard pressed to close the gap as substantial numbers of people at risk for malaria live largely outdoors. Many do not wish to be offered malaria treatment or even to be found by government or non-government organizations. To gain cooperation in relatively docile Pailin, Bill Gates said those participating “were paid a day’s wages, the equivalent of about $2.50, and got a free lunch.”

About 1,700 people were processed, but the program would need to be scaled up to reach 4 million people in Cambodia, according to Gates. “We have to clear the parasites of all the humans in an area,” Gates said, making no exclusion for pregnancy. “Eradication is an ambitious goal,” concluded Gates. “It is a goal to which we remain 100% committed.”

'Radical cure' and pregnancy

Pregnancy might pose some difficulties for eradication. The Gates Foundation’s strategy calls for a “complete cure,” a new drug able to clear malaria infections in one dose, unlike today’s three-day regimen. However, the more radical the cure, the greater the potential impact on pregnancies.

Fortunately, one leading candidate, OZ439, looks far better than artemisinin: “OZ439 is 100 times safer,” according to Tim Wells, Chief Scientific Officer at the Medicines for Malaria Venture (MMV). Wells did not point to a paper or adduce evidence for his statement.

Another highly promising drug, KAE609, presents more of a mystery—even to Wells. Although KAE609 originated from a partnership of MMV and Novartis, the drug company re-possessed its intellectual property after discovering the considerable promise and commercial prospects of KAE609. The rest of the world and even Wells are now on the outside looking in. Novartis apparently has safety data but “has not talked about them externally,” according to Wells.

In early studies, KAE609 was given in multiple smaller doses: three times, 30 milligrams per dose, “which gives a certain plasma exposure,” said Wells. More recently, aiming for radical cure, a single dose of 75 milligrams has been tested. “If they have to go with the higher number," 2.5 times higher, "the safety margin is of course a little bit lower,” observed Wells.

Two other drug candidates are in development, providing a quite remarkable and impressive range of options. “The key will be that we can’t design molecules safe for pregnancy," said Wells, "but we can at least pick the most likely candidates, now that we have a little bit of choice.” 

The choice will be important. More mass drug administrations are likely. According to Bernard Nahlen, "the countries which have eliminated up to this point have not done so without MDA." Nahlen is the Deputy Coordinator of the President's Malaria Initiative. Also, malaria diagnostics aren’t sensitive enough to find low level infections. To clear every infection, including those that are undetectable, eradication would mean “treating” even the uninfected and the possibly pregnant. According to Wells, “for MDA where the subjects don’t have the disease, we need to be looking at vaccine levels of safety – say one serious adverse event in 20,000 cases.” 

However, given current practices which elide or ignore pregnancy concerns in Southeast Asia, global malaria eradication might expose much of a generation in Sub-Saharan Africa to antimalarials, whether artemisinin or new drugs in the pipeline, whose effects on pregnancy and development are not fully understood.


Article history:

[7/22/2015 2:46 PM] Quotation from Bernard Nahlen added

Complete detection: vaporware comes to malaria diagnostics

Rapid diagnostic test: 1,000 times too insensitive to detect all malaria infections (Photo: Wikimedia)

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.

Billions served

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]

Have we already seen the best malaria vaccine prospects?

For half a century, scientists century have known one weird trick for eliciting immunity to malaria:  allow a person to be bitten 1,000 times by mosquitoes that have been irradiated. It works. In 1967, researchers reported sterilizing protection in mice from this approach. One thousand bites worked in later human experiments too, eliciting protection in 90% of the small group tested. Decades of malaria research has focused on bottling up the irradiation magic into a vaccine. But the most promising leads have been tried without success, raising the question: is the best yet to come? Or are we scraping the bottom of the barrel?

Malaria infection starts with the bite of a malaria-carrying mosquito which injects malaria spores (“sporozoites”) into humans. Radiation-damaged sporozoites, however, prompt a highly protective immune response while being too weak to survive and develop into disease.

A sporozoite consists of more than one thousand response-provoking, antibody generators or “antigens.” In the 1980s, scientists examined the successful antibody responses to the irradiated sporozoites. The winner, going away, was CSP or circumsporozoite protein. Other antigens were discovered too, with acronyms like TRAP and LSA-1. But none dominated the immune response like CSP, making it the clear favorite for a vaccine that only presented the parts of the parasite needed to elicit immunity, a “subunit” vaccine.

The CSP gene was sequenced, also way back in the 1980s, and optimism ran high that a vaccine was within reach. Much lengthy and laborious research eventually produced a candidate vaccine based on CSP called RTS,S. It was “the logical extension of more than a decade of research built on the hypothesis that a subunit vaccine based on the CS protein would protect humans from malaria infection,” as the vaccine’s co-inventor, W.R. Ballou, put it.

In 1997, RTS,S protected a remarkable 6 out of 7 people. However, fast forward years and hundreds of millions of dollars to 2014, and field trials now show the once-promising RTS,S protects only a disappointing 28% of children vaccinated. Although based on CSP, the champion of antigens, RTS,S delivered less than a third of the 90% benefit promised by the whole organism approach.

Many different approaches, combinations, formulations and technologies have been tried but none have produced a vaccine as good as even the mediocre RTS,S. Malaria researchers have helped pioneer a number of different technologies like the use of viruses and DNA as delivery vehicles. Adjuvants, used to amplify immune responses, have also been varied and are still being tested to see if they can improve the protective benefit of different vaccine candidates.

However, in recent years, little new ground has been broken. “A lot of people have been focused on various formulations with the currently available candidates,” said Lee Hall, Chief of the Parasitology & International Programs Branch at the National Institutes of Health. “There was some ramp up as people looked at a number of different ones. But if they didn’t pan out in the early studies then they weren’t moved forward.”

Among alternative to CSP, only one antigen, based on TRAP, is now in Phase IIb clinical trials. The vaccine protected only 13% of vaccinees in an earlier study. There is one other single-antigen candidate, FMP012, that has pending results from a Phase I trial. Mainly, however, vaccines aimed at protecting against malaria infection are overwhelmingly variations on CSP, both in the PATH Malaria Vaccine Initiative pipeline and the World Health Organization “Rainbow” table. Some projects combine RTS,S with other vaccines, in search of additive or synergistic effect. Also, scientists recently succeed in making a full-length CSP for study. (RTS,S only uses a portion of CSP.)

Many combinations are possible and the number of antigens could be increased, although technical and regulatory issues begin to arise. “Obviously people want to go for something is likely to be successful,” said Lee Hall. “They don’t want to embark on something that is so complex at the outset that the chances of it making it through the development process is low.” How many antigens a subunit vaccine could deliver is not known. According to Hall: “If it turns out that it’s two or five, that might [be] possible to do. If it turns out you need 50, then it turns out to be a lot more difficult.”

Some scientists see the failure of RTS,S as the undoing of the subunit approach. The success of the irradiated sporozoites served “as justification for the ensuing decades of research aimed at identifying the ‘right’ vaccine antigen,” or antigens wrote Mahamadou Thera and Christopher Plowe. “[I]t is reasonable to believe that it may be possible to construct a multistage, multi-antigen recombinant protein that improves on the efficacy of RTS,S,” they continue. But Plowe is skeptical that high levels of protection are possible. In a book chapter version of the article, Plowe added: “it seems not unlikely that vaccines that target 2, 5, or even 15 of the 5,000 gene products will still fall short of the high levels of protection seen with radiation-attenuated whole-organism vaccines when delivered through the bites of infected mosquitoes.”

According to Timothy Wells, Chief Scientific Officer at the Medicines for Malaria Venture, RTSS “even as a partial vaccine, is a massive triumph immunologically.” The human immune response to malaria is transient and requiring, on some estimates, 10 malaria infections, according to Wells. “This is why making a vaccine is close to impossible,” said Wells. Perhaps informed by this conclusion, the PATH Malaria Vaccine Initiative (MVI), funded by the Gates Foundation, has been quietly dropping candidate after candidate. Two projects testing multiple antigens have been dropped, one as long ago as December. However, that cancelation was only recently reflected in MVI’s portfolio which “was just updated last week,” the week of May 10, according to PATH spokesperson, Kelsey Mertes. One other canceled vaccine project “is still included on the portfolio because it hasn’t been closed out yet,” according to Mertes. Cancelled projects remain in the portfolio “until the contract is closed out and the last payment made,” Mertes explained. The portfolio still contains two studies of RTS,S given with another vaccine. Results are in for one but, perhaps suggesting the outcomes were not spectacular, Mertes did not reply to an email asking if it would move forward into the next phase of trials. The MVI portfolio looks increasingly barren as the sole remaining active trial for a protective pre-erythrocytic vaccine will report results later this year.

The search continues technically, although at the very earliest stage of the pipeline with any actual vaccine many years away. According to Mertes, MVI “is undertaking target validation work” on over 25 candidate antigens for a protective, pre-erythrocytic vaccine. However, science suggests that future discovery of a highly protective antigen or antigens is unlikely. Malaria has some 5,000 genes, but there are not 5,000 potential vaccine targets. Malaria genes produce just under 2,000 proteins. Vaccine targets are fewer still because not all the proteins are seen by the human immune system. Indeed, according to Stefan Kappe: “The number of surface and secreted proteins we identified is much lower, less than 100.” Kappe leads a group at Seattle Biomed that began assessing new antigen candidates in late 2012 for MVI. The project is expected to take six years or more. “Most of the novel targets are not published yet,” said Kappe.

It is not the first such effort but, because of its comprehensiveness, it could be the last.

In 2011, a group at New York University published results of efforts, supported by the Gates Foundation and others, to find new candidate antigens for a malaria vaccine. The researchers tested 34 new antigens, but concluded: “In summary, we failed in our attempt to discover powerful protective non-CS antigens…” Researchers saw no reason to look any further for other antigens. The study’s lead author, Satish Mishra, wrote in email: “We can’t rule out the possibilities in science but we as far as we understand it’s very unlikely” that there are important, yet to-be-discovered antigens. More bluntly, according to Mishra: “We have already checked the best candidates and already given up the new candidate search.”

Claim of Possible Drug-Resistant Malaria in Angola Withdrawn

A paper reporting a possible case of drug-resistant malaria in Angola appeared last July (reported here), meeting with scathing incredulity and direct calls for retraction from the World Health Organization and some members of the malaria research community.

The surprising firefight appears to have been concluded, not with retraction but the publication of letters from the authors of the original paper and its detractors at WHO and Mahidol University. The paper’s authors now acknowledge that “our report of a Vietnamese worker returning from Angola with severe Plasmodium falciparum malaria not responsive to artemisinins is unlikely to indicate that artemisinin resistance has reached Angola.”

The paper and letters appeared in Emerging Infectious Diseases, published by the Centers for Disease Control (CDC).

Critics point out that the delayed clearance time seen in the case was nearly ten times slower than that seen in drug-resistant malaria in Southeast Asia, the only region in the world with clinically-verified resistance to artemisinin-based anti-malarials. Genetic testing after the publication of the paper did not find any of the mutations in the K13 gene associated with resistance. Also, the drug used in the case came from a batch that was withdrawn because of quality issues.

In rebuttal, the authors of the original paper note that the drug used, while substandard was far from lacking any activity. The paper is not being withdrawn and the case is not closed, say the authors: “the reasons for the lack of response to artemisinins in this patient remain unknown and are under continued investigation.”

WHO also says it is still looking into the same geographic area of Angola from which the disputed case originated.

Olivo Miotto, who previously predicted the paper would be retracted, said more recently “it was a mess-up, as was suspected at the time by those more interested in science than fiction.”

According to Annette Erhart, one of the paper’s authors, the Vietnamese investigators knew that publishing the case would expose them “to criticisms about the way the patient was managed.” The group published nonetheless because “for the first time, they were confronted to a situation where AS [artesunate] did not work at the dosage recommended by the national guidelines.” Continued Erhart: “The attitude of the WHO is discouraging anybody to report suspected resistance cases, while it should be actually the opposite.”

WHO’s Pascal Ringwald, contacted last September about the case, said “Globally it is amazing how journalists misunderstand artemisinin resistance and they do not investigate on what should be investigated.” Although the paper had been published by the CDC and elicited public statements of concern from prominent malaria researchers, Ringwald insisted on his own knowledge: “I do not know which is or are your sources but I think that you do not trust me.” The case, he said, "is absolutely not interesting and not important.” Ringwald forbade all further inquiries: “In the future please use your other sources of info and do not contact me for any kind of reason.”

A ceasefire of sorts appears to have been brokered. Said Miotto: “I think everyone is just letting it drop—not worth any arguments.” Patrick Kachur, chief of malaria at the CDC, declined to answer questions about the matter directly, referring inquiries to the CDC press office. Kachur did allow that “I was hoping these [letters] would be ready to share a lot sooner.” 

Malaria vaccine disappoints, shifts strategy for eradication

Five years ago, many in the malaria field believed eradication would be “impossible” without an effective vaccine. However, Bill Gates’ 2015 annual letter proposed dispatching malaria “within a generation,” not through vaccination but mass screening and drug administration. In it, Gates relegated vaccines from the front lines to a mop up role, less protecting people from malaria than preventing further transmission in the event of infection, “so that once an area is cleared of the parasite, it stays clear.” 

Vaccines are much fallen.

Read the rest at Humanosphere

Bednets failing to reduce malaria in Uganda, maybe everywhere

Since 2000, billions of dollars have been spent on a massive and multipronged anti-malaria effort supported by the World Health Organization, groups like Nothing But Nets, the Global Fund to Fight AIDS, TB and Malaria and other organizations. As a result, WHO says, malaria mortality has fallen by about 50 percent globally in the past 15 years.

But how certain are we of this success story, and what’s really driving it? Is it the hundreds of millions of bednets?

“That’s the million dollar question,”  said Moses Kamya, speaking recently at the University of Washington’s Institute for Health Metrics and Evaluation (IHME) in Seattle.

Kamya is a professor of medicine at Makerere University in Uganda. He presented an unpublished study showing persistently high transmission and increasing incidence of malaria in rural Uganda despite universal bednet coverage and effective anti-malaria treatment.

Kamya findings suggest that some experts are quietly, sometimes reluctantly, beginning to dig deeper into the assumption that bednets are as effective as claimed.

Read the rest at Humanosphere...